V1b receptor antagonist for use in the treatment of patients having an elevated avp level and/or an elevated copeptin level

ABSTRACT

The present invention relates to a vasopressin receptor 1B (V 1B ) antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in patients showing an elevated arginine vasopressin (AVP) level and/or an elevated copeptin level. The present invention further relates to a method for predicting the treatment response to a V 1B  antagonist in patients with depressive symptoms and/or anxiety symptoms.

FIELD OF THE INVENTION

The present invention relates to a vasopressin receptor 1B (V_(1B))antagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in patients showing an elevated arginine vasopressin(AVP) level and/or an elevated copeptin level. The present inventionfurther relates to methods for predicting a treatment response to aV_(1B) antagonist in patients with depressive symptoms and/or anxietysymptoms.

BACKGROUND OF THE INVENTION

Hypotheses as to the development of depression and anxiety disordersinter alia point to the role of neuropeptides, which are involved in thecentral regulation of stress hormones. Besides corticotropin releasinghormone, vasopressin may also play an important role in this respect(Griebel and Holsboer (2012); Neuropeptide receptor ligands as drugs forpsychiatric diseases: the end of the beginning?; Nat Rev Drug Discov 11:462-479).

Vasopressin (also referred to as arginine vasopressin (AVP), vasopressinargipressin or antidiuretic hormone (ADH)) is a neuropeptide which issynthesized in the hypothalamus of mammals and exerts its action throughdifferent receptors, e.g. the V_(IA) and V_(1B) receptor subtype widelydistributed in the central nervous system (CNS) (Griebel and Holsboer(2012); Neuropeptide receptor ligands as drugs for psychiatric diseases:the end of the beginning?; Nat Rev Drug Discov 11: 462-479).

In human studies the hypothesis that vasopressin plays an important rolein depression and anxiety disorders is supported by increased AVPsecretion from hypothalmatic neurons. Animal experiments also point to acentral role of vasopressin in the development of depression and anxietydisorders (Landgraf (2006); The Involvement of the Vasopressin System inStress-Related Disorders; CNS & Neurological Disorders 5:167-179).

These findings lead to research and development programs of thepharmaceutical industry aiming at the development of vasopressinantagonists useful in the treatment of depression and/or anxietydisorders. However, so far clinical trials have been unsuccessful.

Hence, there is still a need for antidepressant and/or anxiolytic drugseffective in the treatment of depressive symptoms and/or anxietysymptoms in a number of psychiatric disorders as well as for methods forpredicting treatment responses to V_(1B) antagonists in patientssuffering from depressive and/or anxiety symptoms.

SUMMARY OF THE INVENTION

It has now been found that despite the so far unsuccessful clinicaltrials, a specific group of patients showing depressive symptoms and/oranxiety symptoms, i.e. patients showing an elevated arginine vasopressinlevel and/or an elevated copeptin level, profits from the treatment withV_(1B) antagonists.

It has also been found that the treatment response to V_(1B) antagonistscan be predicted by determining the copeptin concentration in a bloodsample of a patient and/or by determining the AVP concentration in asample of cerebrospinal fluid of said patient.

A further finding of the invention is that the presence of a polymorphicvariant in the vasopressin receptor 1B (AVPR1B) gene in combination withone or more further marker(s) is indicative for an elevated argininevasopressin level and/or copeptin level and thus for a treatmentresponse to V_(1B) antagonists.

In one aspect the present invention relates to a vasopressin receptor 1B(V_(1B)) antagonist for use in the treatment of depressive symptomsand/or anxiety symptoms in a patient showing an elevated argininevasopressin (AVP) level and/or an elevated copeptin level. For example,the present invention relates to a V_(1B) receptor antagonist for use inthe treatment of depressive symptoms and/or anxiety symptoms in apatient showing an elevated AVP level. According to another exemplaryembodiment, the present invention relates to a V_(1B) receptorantagonist in the treatment of depressive symptoms and/or anxietysymptoms in a patient showing an elevated copeptin level. In anotherexemplary embodiment, the present invention relates to a V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and anelevated copeptin level.

In one embodiment the present invention relates to the V_(1B) receptorantagonist for use as described above, wherein the elevated AVP leveland/or the elevated copeptin level in said patient is determined bymeans of measurement of AVP and/or by means of copeptin measurement.

In a specific embodiment of the invention, the copeptin measurement isperformed in a blood sample of said patient.

Thus, in one embodiment the present invention relates to a vasopressinreceptor 1B (V_(1B)) antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated levelof copeptin in the blood.

In another embodiment of the invention, the patient has been pre-treatedwith dexamethasone prior to performance of the copeptin measurementand/or measurement of AVP.

A further embodiment of the invention relates to the V_(1B) receptorantagonist for use as described above, wherein an elevated AVP level isindicated by a copeptin blood concentration of at least 5 pmol/L,optionally in the range from 5 to 7 pmol/L.

A specific embodiment of the invention relates to the V_(1B) receptorantagonist for use as described above, wherein the AVP measurement isperformed in a sample of cerebrospinal fluid of said patient.

Thus, in one embodiment the present invention relates to a vasopressinreceptor 1B (V_(1B)) antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated levelof AVP in the cerebrospinal fluid.

In another embodiment of the invention, the patient showing an elevatedAVP level has an AVP concentration of at least 4 pg/ml AVP, optionallyin the range from 4 to 6 pg/ml AVP.

A further embodiment of the invention relates to a V_(1B) receptorantagonist for use as described herein, wherein an elevated AVP leveland/or an elevated copeptin level is detected by determining thepresence or absence of at least one polymorphic variant in the AVPR1Bgene in combination with the presence or absence of at least onepolymorphic variant in the patient's genome excluding the AVPR1B gene.

In one embodiment, the polymorphic variant in the AVPR1B gene and/or inthe patient's genome excluding the AVPR1B gene is a single nucleotidepolymorphism (SNP).

In particular, the polymorphic variant in the AVPR1B gene is SNPrs28373064, which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 2, wherein in one or two alleles of thewild-type nucleotide A is replaced by indicator nucleotide G.

In another embodiment, the at least one polymorphic variant in thepatient's genome excluding the AVPR1B gene is selected from the group ofbiomarkers comprising:

-   -   SNP rs9880583 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 3, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide G,    -   SNP rs13099050 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 4, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide C,    -   SNP rs7441352 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 5, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs730258 which is represented by a single polymorphic change        at position 27 of SEQ ID NO: 6, wherein in one or two alleles        the wild-type nucleotide C is replaced by indicator nucleotide        T,    -   SNP rs12654236 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 7, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs17091872 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 8, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs12254219 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 9, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs11575663 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 10, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs7080276 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 11, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs7416 which is represented by a single polymorphic change        at position 27 of SEQ ID NO: 12, wherein in one or two alleles        the wild-type nucleotide A is replaced by indicator nucleotide        G,    -   SNP rs12424513 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 13, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs1035050 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 14, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs9959162 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 15, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide C, and/or    -   SNP rs8088242 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 16, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G.

Another embodiment of the invention relates to a V_(1B) receptorantagonist for use as described herein, wherein the group of biomarkerscomprises at least 2, at least 5, at least 8 or at least 11 of thebiomarkers defined herein as polymorphic variants in the patient'sgenome excluding the AVPR1B gene.

In another embodiment, the group of biomarkers consists of thebiomarkers as defined herein as polymorphic variants in the patient'sgenome excluding the AVPR1B gene.

In a further embodiment, the combination of the presence or absence ofSNP rs28373064 with at least 1, at least 2, at least 3, at least 4, atleast 5, at least 6, at least 7, at least 8, at least 9, at least 10, atleast 11, at least 12, at least 13 or all of the biomarkers as definedherein as polymorphic variants in the patient's genome excluding theAVPR1B gene is determined.

In yet another embodiment, the presence of SNP rs28373064 in combinationwith the presence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNPrs17091872, SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416,SNP rs1035050, SNP rs9959162 and SNP rs8088242 is determined. In yetanother embodiment the absence of SNP rs28373064 in combination with theabsence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 isdetermined. In yet another embodiment, the presence of SNP rs28373064 incombination with the presence of SNP rs9880583, SNP rs730258, SNPrs12654236, SNP rs17091872, SNP rs12254219, SNP rs11575663, SNPrs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162 and SNP rs8088242and the absence of SNP rs28373064 in combination with the absence of SNPrs13099050, SNP rs7441352 and SNP rs12424153 is determined.

A further embodiment of the invention relates to a V_(1B) receptorantagonist for use as described above, wherein the V_(1B) antagonist isselected from the group consisting of SRR149415 (SSR149415), Org 52186,ABT-436 and/or ABT-558.

In another embodiment of the invention, the V_(1B) receptor antagonistfor use as described above is administered in combination with at leastone further pharmaceutically active compound suitable for the treatmentof depressive symptoms and/or anxiety symptoms.

In a specific embodiment of the invention, the at least one furtherpharmaceutically active compound is selected from selective serotoninreuptake inhibitors, serotonin-norepinephrine reuptake inhibitors,dopamine reuptake inhibitors, noradrenergic and specific serotonergicantidepressants, norepinephrine (noradrenaline) reuptake inhibitors,selective serotonin reuptake enhancers, norepinephrine-dopaminedisinhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclicantidepressants, tetracyclic antidepressants, monamine oxidaseinhibitors, psychostimulants, mood stabilizers, amine precursors,serotonin antagonists and reuptake inhibitors, anticonvulsants,nicotine, phytopharmaceuticals, melatonin receptor antagonists, 5-HTantagonists, benzodiazepines, buspirone, azapirones, barbiturates,hydroxyzine, pregabalin, corticotropin-releasing hormone receptorantagonists, neurokinin receptor antagonists, oxytocin andglucocorticoid receptor antagonists.

Another embodiment of the invention relates to the V_(1B) receptorantagonist for use as described above, wherein the treatment response tothe V_(1B) receptor antagonist is predicted by the method as describedbelow.

Another aspect relates to a method for predicting a treatment responseto a V_(1B) receptor antagonist in a patient with depressive symptomsand/or anxiety symptoms comprising the following steps:

-   (i) determining the presence or absence of at least one polymorphic    variant in the AVPR1B gene in a nucleic acid sample of said patient    and-   (ii) determining the presence or absence of at least one polymorphic    variant in the patient's genome excluding the AVPR1B gene in a    nucleic acid sample of said patient,    wherein the presence or absence of at least one polymorphic variant    in the AVPR1B gene in combination with the presence or absence of at    least one polymorphic variant in the patient's genome excluding the    AVPR1B gene is indicative for the treatment response.

In one embodiment of said method the polymorphic variant in the AVPR1Band/or in the patient's genome excluding the AVPR1B gene is a singlenucleotide polymorphism (SNP). For example, the polymorphic variant inthe AVPR1B gene is an SNP. In another exemplary embodiment, thepolymorphic variant in the patient's genome excluding the AVPR1B gene isan SNP.

In yet another embodiment, a polymorphic variant in the AVPR1B gene isSNP rs28373064 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 2, wherein in one or two alleles of thewild-type nucleotide A is replaced by indicator nucleotide G.

In a further embodiment, the at least one polymorphic variant in thepatient's genome excluding the AVPR1B is selected from the group ofbiomarkers comprising:

-   -   SNP rs9880583 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 3, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide G,    -   SNP rs13099050 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 4, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide C,    -   SNP rs7441352 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 5, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs730258 which is represented by a single polymorphic change        at position 27 of SEQ ID NO: 6, wherein in one or two alleles        the wild-type nucleotide C is replaced by indicator nucleotide        T,    -   SNP rs12654236 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 7, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs17091872 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 8, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs12254219 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 9, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs11575663 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 10, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs7080276 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 11, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs7416 which is represented by a single polymorphic change        at position 27 of SEQ ID NO: 12, wherein in one or two alleles        the wild-type nucleotide A is replaced by indicator nucleotide        G,    -   SNP rs12424513 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 13, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs1035050 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 14, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs9959162 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 15, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide C, and/or    -   SNP rs8088242 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 16, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G.

Another embodiment of the present invention relates to the methodaccording to the invention, wherein the group of biomarkers for whichthe presence or absence is determined wherein the group of biomarkerscomprises at least 2, at least 5, at least 8 or at least 11 of thebiomarkers in the patient's genome excluding the AVPR1B gene definedherein. For example, the presence or absence of at least 2, at least 5,at least 8 or at least 11 polymorphic variants or biomarkers as definedabove is determined in step (ii) of the method described above.

In a further embodiment, the group of biomarkers for which the presenceor absence is determined consists of the biomarkers in the patient'sgenome excluding the AVPR1B gene defined herein. For example, thepresence or absence of all 14 polymorphic variants or biomarkers in thepatient's genome excluding the AVPR1B gene as defined above aredetermined in step (ii) of the method described above.

In another embodiment, the combination of the presence or absence of SNPrs28373064 with the presence or absence of at least 1, at least 2, atleast 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, at least 10, at least 11, at least 12, at least 13 or all ofthe biomarkers in the patient's genome excluding the AVPR1B gene asdefined herein is determined.

In yet another embodiment, the presence of SNP rs28373064 in combinationwith the presence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNPrs17091872, SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416,SNP rs1035050, SNP rs9959162 and SNP rs8088242 is determined. In yetanother embodiment the absence of SNP rs28373064 in combination with theabsence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 isdetermined. In one embodiment, the presence of SNP rs28373064 incombination with the presence of SNP rs9880583, SNP rs730258, SNPrs12654236, SNP rs17091872, SNP rs12254219, SNP rs11575663, SNPrs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162 and SNP rs8088242and the absence of SNP rs28373064 in combination with the absence of SNPrs13099050, SNP rs7441352 and SNP rs12424153 is determined.

Another aspect of the invention relates to a method for predicting atreatment response to a V_(1B) receptor antagonist in a patient withdepressive symptoms and/or anxiety symptoms, wherein the copeptinconcentration in a blood sample of said patient is determined and/or theAVP concentration in a sample of cerebrospinal fluid of said patient isdetermined and wherein an elevated copeptin and/or an elevated AVPconcentration is indicative for a patient responding to a treatment witha V_(1B) receptor antagonist.

In another embodiment of the invention, the above method furthercomprises a step of pre-treating the patient with dexamethasone andsubsequently determining the copeptin concentration in the blood sampleand/or the AVP concentration in the sample of cerebrospinal fluid.

In a further embodiment of the invention, the above described methodfurther comprises subjecting the patient to at least one combineddexamethasone/corticotropin releasing hormone test (dex/CRH test).

In another embodiment of the above described method, the copeptinconcentration indicative for a patient responding to a treatment with avasopressin receptor antagonist is at least 5 pmol/L, optionally in therange of 5-7 pmol/L.

In a further embodiment of the above described method, the elevated AVPconcentration indicative for a patient responding to a treatment with aV_(1B) receptor antagonist is at least 4 pg/ml AVP, optionally 4 to 6pg/ml AVP.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Plasma copeptin levels at the first dex/CRH test in 75 patientswith low and 75 patients with high HPA axis dysregulations according tothis test.

FIG. 2: Graph of the phenotypic distribution of ln(AAUC) at in-patientadmission. The X-axis shows the ln of the AUC of the ACTH response andthe Y-axis the frequency in total N/bin. #

DETAILED DESCRIPTION OF THE INVENTION

Where the term “comprise” or “comprising” is used in the presentdescription and claims, it does not exclude other elements or steps. Forthe purpose of the present invention, the term “consisting of” isconsidered to be an optional embodiment of the term “comprising of”. Ifhereinafter a group is defined to comprise at least a certain number ofembodiments, this is also to be understood to disclose a group whichoptionally consists only of these embodiments.

Where an indefinite or a definite article is used when referring to asingular noun such as “a” or “an” or “the”, this includes a plural formof that noun unless specifically stated. Vice versa, when the pluralform of a noun is used it refers also to the singular form. For example,when V_(1B) antagonists are mentioned, this is also to be understood asa single V_(1B) antagonist.

Furthermore, the terms first, second, third, (a), (b), (c) or (i), (ii),(iii) and the like in the description and in the claims are used fordistinguishing between similar elements and not necessarily fordescribing a sequential or chronological order. Also, if method stepsare described herein in a certain order, it is to be understood thatsaid steps do not necessarily have to be performed in the describedsequential or chronological order. It is to be understood that the termsso used or the method steps described are interchangeable underappropriate circumstances and that the embodiments of the inventiondescribed herein are capable of operation in other sequences thandescribed or illustrated herein.

As used herein “modulation of the receptor mediated activity” includesblocking of the receptor mediated activity as well as increasing thereceptor mediated activity.

Further definitions of the terms will be given below in the context ofwhich the terms are used.

While so far clinical trials have failed to demonstrate the superiorityof V_(1B) antagonists in the treatment of depression and/or anxietysymptoms, it has now been found that a certain patient group showingdepressive symptoms and/or anxiety symptoms, i.e. patients showing anelevated arginine vasopressin level and/or an elevated copeptin level,is responsive to the treatment with V_(1B) antagonists.

Hence, in one aspect the present invention relates to a V_(1B)antagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated arginine vasopressin(AVP) level, e.g. an elevated AVP level in the cerebrospinal fluid.

In another aspect the present invention relates to a V_(1B) antagonistfor use in the treatment of depressive symptoms and/or anxiety symptomsin a patient showing an elevated copeptin level, e.g. an elevatedcopeptin level in the blood.

A further aspect of the present invention relates to a V_(1B) antagonistfor use in the treatment of depressive symptoms and/or anxiety symptomsin a patient showing both, an elevated arginine vasopressin level and anelevated copeptin level.

The patient showing an elevated AVP and/or an elevated copeptin levelmay be a patient showing depressive symptoms. Alternatively, the patientshowing an elevated AVP and/or an elevated copeptin level may be apatient showing anxiety symptoms. Alternatively, the patient showing anelevated AVP and/or an elevated copeptin level may be a patient showingboth, depressive and anxiety symptoms.

Depressive symptoms comprise inter alia low mood, low self-esteem, lossof interest or pleasure, psychosis, poor concentration and memory,social isolation, psychomotor agitation/retardation, thoughts of deathor suicide, significant weight change (loss/gain), fatigue, and afeeling of worthlessness. The depressive disorders can last for weeks tolifelong disorder with periodic reoccurring depressive episodes. For theassessment of depression severity (e.g. moderate or severe depression)the Hamilton Depression Rating Scale (HAM-D) (Hamilton, J NeurolNeurosurg Psychiatry, 1960) may be used. The depression mode may be alsorated by alternative scales as the Beck Depression Inventory (BDI), theMontgomery-Äsberg Depression Scale (MADRS), the Geriatric DepressionScale (GDS), the Zung Self-Rating Depression Scale (ZSRDS). It isunderstood within the meaning of the invention that the V_(1B)antagonist for use as described herein can be used in the treatment ofany of the above mentioned depressive symptoms or a combination of anyof the above mentioned depressive symptoms in a patient showing anelevated arginine vasopressin level and/or an elevated copeptin level.

Anxiety symptoms comprise inter alia panic disorders, generalizedanxiety disorder, phobias and posttraumatic stress disorder. Typicalsymptoms of anxiety are avoidance behavior which may lead to socialisolation, physical ailments like tachycardia, dizziness and sweating,mental apprehension, stress and tensions. The strength of these symptomsranges from nervousness and discomfort to panic and terror in humans oranimals. Most anxiety disorders may last for weeks or even months, someof them even for years and worsen if not suitably treated. For measuringthe severity of anxiety symptoms, the Hamilton Anxiety Rating Scale(HAM-A) or the State-Trait Anxiety Rating Scale (STAI) can be used. Itis understood within the meaning of the invention that the V_(1B)receptor antagonist for use as described herein can be used in thetreatment of any of the above mentioned anxiety symptoms or acombination of any of the above mentioned anxiety symptoms in a patientshowing an elevated arginine vasopressine level and/or an elevatedcopeptin level.

Also, the V_(1B) receptor antagonists can be used for the treatment of apatient suffering from any of the depressive symptoms described hereinand any of the anxiety symptoms as described herein showing an elevatedarginine vasopressine level and/or an elevated copeptin level.

“Healthy individual” as used herein, denotes any person not sufferingfrom anxiety and/or depressive symptoms. In particular, a healthyindividual denotes any person having a score of 0-7 according to theHamilton Depression Rating Scale and/or a score of 0-6 on theMontgomery-Äsberg Depression Scale and/or a score of 20-44 on the ZungSelf-Rating Depression Scale and/or a score of less than 14 on theHamilton Anxiety Rating Scale. In addition, or alternatively, a healthyindividual denotes any person having a score considered to be normal inany of the known scales for assessment of depression and/or anxiety.

The neuropeptide arginine vasopressin (also denoted as vasopressin,vasopressin argipressin or antidiuretic hormone (ADH)) is a nonapeptidewhich is produced in the paraventricular nucleus of the hypothalamus andthe supraoptic nucleus. Vasopressin has the following sequence, wherebyCys and Cys are connected via an intramolecular disulfide bond:

(SEQ ID NO: 1) Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂

Patients showing elevated arginine vasopressin levels as used hereininclude patients showing an increased gene activity of genes coding forAVP. In addition or alternatively, patients showing elevated AVP levelsas used herein may include patients showing a combination of thepresence or absence of at least one polymorphic variant of genes codingfor the arginine vasopressine receptor (AVPR), in particular for thearginine vasopressine receptor 1B (AVPR1B), with the presence or absenceof at least one polymorphic variant in the patient's genome excludingthe AVPR1B gene as defined herein. Patients showing elevated argininevasopressin levels also include patients showing elevated levels of AVPin the cerebrospinal fluid and/or patients showing elevated blood levelsof AVP. Specifically, the patients showing an elevated AVP level show anelevated central AVP level, i.e. elevated AVP concentrations in the CNS.

In one embodiment the present invention relates to a V_(1B) receptorantagonist for use as described herein, wherein an elevated AVP level insaid patient is determined by means of AVP measurement. The measurementof AVP may be performed in a sample of cerebrospinal fluid of saidpatient. Samples of cerebrospinal fluid can be obtained from the patientby any method known in the art, e.g. by lumbar puncture.

Methods for determination of AVP levels in a sample of cerebrospinalfluid of a patient are known in the art and include immunoassays, e.g.radioimmunoassays. Hence, in one embodiment of the invention the AVPlevel in the sample of cerebrospinal fluid of the patient is measured bymeans of immunoassay, optionally by means of radioimmunoassay.

As used herein, an elevated AVP level denotes any AVP level higher thanthe AVP level measured in blood samples and/or samples of thecerebrospinal liquid of healthy individuals. Specifically, an elevatedAVP level in a patient showing depressive symptoms and/or anxietysymptoms is indicated by an AVP concentration in the sample ofcerebrospinal fluid of at least 4 pg/ml AVP, at least 5 pg/ml AVP, atleast 6 pg/ml AVP, at least 7 pg/ml AVP, at least 8 pg/ml AVP, at least10 pg/ml AVP, at least 20 pg/ml AVP, at least 30 pg/ml AVP, at least 50pg/ml AVP, at least 70 pg/ml AVP or at least 90 pg/ml AVP. Elevated AVPlevels may be indicated by an AVP concentration in the sample ofcerebrospinal fluid in the range from 4 to 8 pg/ml AVP, optionally inthe range from 4 to 6 pg/ml AVP.

Copeptin (also denoted as C-terminal proAVP) is a glycopeptide of alength of 39 amino acids which is produced from the C-terminal part ofthe AVP precursor. AVP and copeptin are released from the AVP precursorin an equimolar amount. Since copeptin is stable in blood (i.e. bloodplasma, blood serum and/or whole blood) it provides the advantage thatit may be used as surrogate marker for AVP levels in the blood plasma,blood serum and/or whole blood.

In a further embodiment the present invention thus relates to a V_(1B)receptor antagonist for use as described herein, wherein an elevated AVPlevel and/or an elevated copeptin level in said patient is determined bymeans of copeptin measurement.

Methods for determination of copeptin levels in a blood sample derivedfrom a patient are known in the art and include immunoassays, e.g.sandwich immunoassays. Examples of such immunoassays are the CopeptinEIA Kit provided by BioSupply UK, the Thermo Scientific BRAHMS copeptinKryptor assay and the Thermo Scientific BRAHMS copeptin Kryptor us assayprovided by ThermoScientific.

Hence, in another embodiment of the invention, the AVP level and/orcopeptin level of the patient showing depressive symptoms and/or anxietysymptoms is determined by means of an immunoassay, optionally by meansof a sandwich immunoassay. In another of its embodiments, the copeptinlevel is determined in a blood sample of the patient as defined herein.As used herein, “blood sample” relates to whole blood, blood serumand/or blood plasma. The blood sample can be obtained from the patientby any method known in the art, e.g. with a sterile needle. In aspecific embodiment of the invention, the copeptin level is determinedin the blood plasma derived from the blood sample of said patient. It isknown in the art that blood plasma may be obtained by centrifugation ofa blood sample to which an anti-coagulant has been added.

As used herein, an elevated copeptin level denotes any copeptin levelhigher than the copeptin level measured in blood samples of healthyindividuals. Specifically, an elevated copeptin level and therefore alsoan elevated AVP level in a patient showing depressive symptoms and/oranxiety symptoms is indicated by a copeptin blood concentration of atleast 5 pmol/L, at least 6 pmol/L, at least 7 pmol/L, at least 8 pmol/L,at least 9 pmol/L, at least 10 pmol/ml, at least 20 pmol/ml, at least 30pmol/ml, at least 40 pmol/ml, at least 50 pmol/ml, at least 60 pmol/ml,at least 70 pmol/ml, at least 80 pmol/ml, at least 90 pmol/ml or atleast 100 pmol/ml. Elevated copeptin levels and therefore also elevatedAVP levels may be indicated by a copeptin blood concentration in therange from 5 to 9 pmol/L, optionally in the range from 5 to 7 pmol/L.

It is also encompassed in the invention that both the elevated copeptinlevel and the elevated AVP level are determined in the patient by meansof copeptin measurement and measurement of AVP.

Furthermore, it has been found that the presence or absence of specificsingle nucleotide polymorphisms in the human genome not including thevasopressin receptor 1B (AVPR1B) gene in combination with the presenceor absence of at least one specific polymorphic variant within thevasopressin receptor 1B (AVPR1B) gene influences the response ofcorticotropin in an endocrine challenge test, e.g. in a combineddexamethasone (dex) suppression/corticotropin releasing hormone (CRH)stimulation test. The combined dex/CRH test has been described by Heuseret al. (The combined dexamethasone/CRH test: a refined laboratory testfor psychiatric disorders., J Psychiatr Res, 1994, 28:341-356) and canbe used for screening for compounds which may be useful in the treatmentof depressive symptoms and/or anxiety symptoms. The dex/CRH test isdescribed further below with respect to the method according to theinvention. A corticotropin (ACTH) increase observed in this combineddexamethasone suppression/corticotropin releasing hormone (CRH)stimulation test can be considered as a surrogate marker for anincreased vasopressin level, thus indicating patients responsive to thetreatment with V_(1B) receptor antagonists. Since specific singlenucleotide polymorphisms in the patient's genome excluding the AVPR1Bgene described herein in combination with a specific polymorphic variantin the AVPR1B gene influence the response of corticotropin in thecombined dex/CRH test, such polymorphic variants may be used foridentifying patients showing depressive and/or anxiety symptoms havingan elevated copeptin and/or vasopressin level and, consequently, showinga treatment response to V_(1B) antagonists.

Thus, in another embodiment, the elevated AVP level and/or copeptinlevel in a patient suffering from depressive and/or anxiety symptoms canbe indicated by determining the combination of the presence or absenceof at least one polymorphic variant in the genes coding for the AVPR1Bin a nucleic acid sample of said patient with the presence or absence ofat least one polymorphic variant in the patient's genome excluding theAVPR1B gene.

A “polymorphic site” or “polymorphic variant” as used herein relates tothe position of a polymorphism or SNP as described herein within thegenome or portion of a genome of a subject, or within a genetic elementderived from the genome or portion of a genome of a subject. In specificembodiments described herein the term “polymorphic variant” relates to asingle nucleotide polymorphism (SNP).

In particular, the polymorphic variant in the AVPR1B gene and/or thepatient's genome excluding the AVPR1B gene is a single nucleotidepolymorphism (SNP). The term “single nucleotide polymorphism” is wellunderstood by the skilled person and refers to a point mutation at acertain position in the nucleotide sequence. In other words, only onenucleotide differs in a certain region.

In a specific embodiment, the polymorphic variant in the AVPR1B gene isSNP rs28373064. Specifically, SNP rs28373064 is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 2, wherein in one or twoalleles of the wild-type nucleotide A is replaced by indicatornucleotide G.

Furthermore, the polymorphic variant in the patient's genome excludingthe AVPR1B gene may be selected from the group of biomarkers comprising:

-   -   SNP rs9880583,    -   SNP rs13099050,    -   SNP rs7441352,    -   SNP rs730258,    -   SNP rs12654236,    -   SNP rs17091872,    -   SNP rs12254219,    -   SNP rs11575663,    -   SNP rs7080276,    -   SNP rs7416,    -   SNP rs12424513,    -   SNP rs1035050,    -   SNP rs9959162, and/or    -   SNP rs8088242.

The SNPs as described herein may be present on the Watson or the Crickstrand, with presence of the corresponding base. If, for example, apolymorphism is present on the Watson strand as A, it is present on theCrick strand as T, if the polymorphism is present on the Watson strandas T, it is present on the Crick strand as A, if the polymorphism ispresent on the Watson strand as G, it is present on the Crick strand asC, and if the polymorphism is present on the Watson strand as C, it ispresent on the Crick strand as G, and vice versa. Also the insertion ordeletion of bases may be detected on the Watson and/or the Crick strand,with correspondence as defined above. For analytic purposes the strandidentity may be defined, or fixed, or may be choose at will, e.g. independence on factors such the availability of binding elements,GC-content etc. Furthermore, for the sake of accuracy, the SNP may bedefined on both strands (Crick and Watson) at the same time, andaccordingly be analyzed.

The term “allele” or “allelic sequence” as used herein refers to aparticular form of a gene or a particular nucleotide, e.g. a DNAsequence at a specific chromosomal location or locus. In certainembodiments of the present invention, a SNP as defined herein may befound at or on one of two alleles in the human genome of a singlesubject. In further specific embodiments, a SNP as defined herein mayalso be found at or on both alleles in the human genome of a singlesubject. The presence of an indicator nucleotide or an indicator tripletas defined herein on both alleles may have a higher predictive valuethan the presence of an indicator nucleotide or an indicator triplet onone allele only, the other allele comprising a wild-type genotype.

The nucleotide that is present in the majority of the population is alsoreferred to as wild-type allele or major allele. The term may furtherrefer to the sequence of the non phenotype-associated allele with thehighest prevalence within a population, e.g. within a Caucasianpopulation. As used herein, this state is defined as “absence of a SNP”.

The specific nucleotide that is present in the minority of thepopulation is also referred as the point mutation, mutated nucleotide orminor allele. As used herein, this state is defined as “presence of aSNP”, “the presence of a polymorphic variant” or “the presence of amarker”.

In theory, the wild-type allele could be mutated to three differentnucleotides. However, the event of a mutation to a first nucleotide inthe reproductive cells of an individual that gets established in apopulation occurs very rarely. The event that the same position ismutated to a second nucleotide and established in the populationvirtually never occurs and can be therefore neglected. Therefore, asused herein, a certain nucleotide position in the genome of anindividual can have two states, the wild-type state (absence of a SNP)and the mutated state (presence of a SNP).

As described above, the combination of the presence or absence of atleast one polymorphic variant in the AVPR1B gene with the presence orabsence of at least one polymorphic variant in the patient's genomeexcluding the AVPR1B gene as described herein in a sample of a patientis indicative for an elevated AVP level and/or an elevated copeptinlevel and, consequently, for a positive treatment response to V_(1B)receptor antagonists. The at least one polymorphic variant in thepatient's genome excluding the AVPR1B gene may be selected from a groupof biomarkers, in particular from a group of SNPs.

The term “biomarker”, as used herein, relates to any nucleic acidsequence of any length, or a derivative thereof, which comprises apolymorphic variant such as the polymorphic variant in the AVPR1B geneor the polymorphic variants in the patient's genome excluding the AVPR1Bgene as defined herein. In particular, the term “biomarker” may relateto SNPs.

In addition to the combination of the presence or absence of the atleast one polymorphic variant in the AVPR1B gene with the presence orabsence of a polymorphic variant in the patient's genome excluding theAVPR1B gene as described herein, the presence of one or more furthermarkers for an elevated AVP and/or copeptin level, such as clinicalmarkers may also be determined.

In the context of the present invention “a set of biomarkers” or “groupof biomarkers” relates to a combination of polymorphic variants in thepatient's genome, including combinations of polymorphic variants in theAVPR1B gene and/or in the patient's genome excluding the AVPR1B gene. Inparticular, such a set or group of biomarkers may relate to a setcomprising at least 2, at least 5, at least 8 or at least 11 of thepolymorphic variants in the AVPR1B gene and/or in the patient's genomeexcluding the AVPR1B gene described herein in Table 1. It is understoodthat the set or group of biomarkers may comprise any further biomarkernot explicitly described herein but considered suitable by the personskilled in the art. In one embodiment of the invention a set/group ofbiomarkers may consist only of the polymorphic variants in the AVPR1Bgene and/or the patient's genome excluding the AVPR1B gene as describedherein in Table 1.

“Combinations of polymorphic variants” as used herein may refer to thepresence or absence of at least one polymorphic variant in the AVPR1Bgene in combination with the presence or absence of a set or group ofpolymorphic variants in the patient's genome excluding the AVPR1B genein a sample of a patient, e.g. to the presence of a combination of apolymorphic variant in the AVPR1B gene in combination with the presenceof 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 polymorphicvariant(s) as described herein for polymorphic variants in the patient'sgenome excluding the AVPR1B gene in Table 1. Combinations of polymorphicvariants may relate to the presence of at least one polymorphic variantin the AVPR1B gene, optionally SNP rs28373064, in combination with thepresence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 polymorphicvariant(s) as described herein in Table 1 for polymorphic variants inthe patient's genome excluding the AVPR1B gene. Combinations ofpolymorphic variants may also relate to the absence of at least onepolymorphic variant in the AVPR1B gene, optionally SNP rs28373064, incombination with the absence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, or 14 polymorphic variant(s) as described herein in Table 1 forpolymorphic variants in the patient's genome excluding the AVPR1B gene.Combinations of polymorphic variants may also relate to the presence ofat least one polymorphic variant in the AVPR1B gene, optionally SNPrs28373064, in combination with the absence of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or 14 polymorphic variant(s) as described herein inTable 1 for polymorphic variants in the patient's genome excluding theAVPR1B gene. Combinations of polymorphic variants may also relate to theabsence of at least one polymorphic variant in the AVPR1B gene,optionally SNP rs28373064, in combination with the presence of 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 polymorphic variants) asdescribed herein in Table 1 for polymorphic variants in the patient'sgenome excluding the AVPR1B gene. In one embodiment, combinations ofpolymorphic variants relate to the presence of at least one polymorphicvariant in the AVPR1B gene, optionally SNP rs28373064, in combinationwith the presence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14polymorphic variant(s) as described herein in Table 1 for polymorphicvariants in the patient's genome excluding the AVPR1B gene. In anotherembodiment, combinations of polymorphic variants relates to the absenceof at least one polymorphic variant in the AVPR1B gene, optionally SNPrs28373064, in combination with the absence of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or 14 polymorphic variant(s) as described herein inTable 1 for polymorphic variants in the patient's genome excluding theAVPR1B gene.

The presence of a combination of polymorphic variants may be associatedwith a specific weighting factor describing the impact of the presenceof such a combination on the prediction of the treatment response to aV_(1B) receptor antagonist. Thus, a specific weighting factor describingthe impact of the presence or absence of such a combination on theprediction of the treatment response to a V_(1B) receptor antagonist maybe associated with the fact that

-   -   at least one polymorphic variant in the AVPR1B gene, optionally        SNP rs28373064, is present and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,        11, 12, 13, or 14 polymorphic variant(s) as described herein in        Table 1 (excluding SNP rs28373064) for polymorphic variants in        the patient's genome excluding the AVPR1B gene is/are present,    -   at least one polymorphic variant in the AVPR1B gene, optionally        SNP rs28373064, is absent and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, or 14 polymorphic variant(s) as described herein in        Table 1 (excluding SNP rs28373064) for polymorphic variants in        the patient's genome excluding the AVPR1B gene is/are absent,    -   at least one polymorphic variant in the AVPR1B gene, optionally        SNP rs28373064, is present and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,        11, 12, 13, or 14 polymorphic variant(s) as described herein in        Table 1 (excluding SNP rs28373064) for polymorphic variants in        the patient's genome excluding the AVPR1B gene is/are absent,    -   at least one polymorphic variant in the AVPR1B gene, optionally        SNP rs28373064, is absent and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, or 14 polymorphic variant(s) as described herein in        Table 1 (excluding SNP rs28373064) for polymorphic variants in        the patient's genome excluding the AVPR1B gene is/are present.

Table 1 provides an overview over SNPs (inside and outside of the AVPR1Bgene) which are, alone or in combination, indicative for an elevated AVPand/or copeptin level and thus for selecting patients suffering fromdepressive and/or anxiety symptoms which should respond to a treatmentwith a V_(1B) antagonist. Hence, in one embodiment, the set or group ofbiomarkers consists of the biomarkers described in Table 1, whereby thepresence or absence of the indicated polymorphic changes (i.e. thepresence of the indicator nucleotides) as described herein is indicativefor an elevated AVP and/or an elevated copeptin level. The term“indicator nucleotide” refers to a non-wild-type nucleotide at positionsof SEQ ID NO: 2 to 16 as described in Table 1.

TABLE 1SNPs (together with flanking sequences) which may be used to predict theresponse to V_(1B) receptor antagonists in patients with depressive symptomsand/or anxiety symptoms. The position of the SNP is indicated as [wild-type nucleotide/indicator nucleotide]. Position of SEQ ID polymorphicSNP_ID Sequence NO change rs28373064 TCCTGCACCGGCTAGCCGGCTGGCAG[A/G]GGG 2 27 CGCGCCAACAGCCGCCAGCCGA rs9880583AAATGAAGCCACTTGTTTCTTCTCCA[C/G]CTAT  3 27 GACCTAGACACCCCCTCCCCArs13099050 AATGAATAAGAAGCCTCTCAAGACAG[A/C]AGG  4 27ATTCAACCTTATAGCTTTGATA rs7441352 TCCTCTCCCCCTATCTCTGCTTTTCA[A/G]CATTG  527 TACTGGAAGTCCTAGCTAAT rs730258 AGAAATAAAATCATTTCATATTCATG[C/T]AATA  627 GATACAAGAAATGTATTAAAG rs12654236 GGACTGTTTTTGTATTCAGTGCACAG[A/G]TGTG 7 27 TGTGAAGACACCCAGCATGTT rs17091872AATGCAAATTTTTATCAAGTACCTAC[A/G]ATGT  8 27 GCGGGCAATTTTGCAAGGTGCrs12254219 CTGTGTCCTTGAAGCCCATGACAGTG[C/T]CTGA  9 27CACAAAGTAGTTGCTCAATAA rs11575663 CTTTATTTACAAAAACAAAACTGCTA[A/G]GCTT 1027 GGCCCAAGGCCCTTATTTGC rs7080276 GTCCACGTGACTTCACACATCAGCCA[A/G]TGAG 1127 GTCTGGCCTCTGTCACCAAAC rs7416 GTAACCGGATGCATTTTTTTNNNNNA[A/G]AATT 1227 TCTCCCTTATCTACTATGATG rs12424513 GCAGCCGGACCCTGTATTGAGGAGGA[C/T]GGG13 27 CAGGGAAAGCATGCTTTAGAGA rs1035050CCTCCCCATCTTTGTATTGATGTAAGC[C/T]TCACC 14 27 TCTCTGCCCACTGGCATCCGrs9959162 TCCTCCTGATTGCCTTCAAATTAGGA[A/C]ATCA 15 27GTTGAAGTTCCTGCTTTCAGA rs8088242 AACATCTGACAAAAGGTAAGAACTCA[A/G]TAA 16 27ATGCTTTGATAGAACTTAAATA

One embodiment of the invention relates to a V_(1B) receptor antagonistfor use in the treatment of depressive symptoms and/or anxiety symptomsin a patient showing an elevated AVP and/or elevated copeptin level,wherein the elevated AVP and/or elevated copeptin level is detected orcan be indicated by determining combinations of the presence or absenceof at least one polymorphic variant in the AVPR1B gene with at least onepolymorphic variant in the patient's genome excluding the AVPR1B gene asdescribed in Table 1.

In yet another embodiment, the presence of SNP rs28373064 in combinationwith the presence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNPrs17091872, SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416,SNP rs1035050, SNP rs9959162 and SNP rs8088242 is indicative for atreatment response to a V_(1B) receptor antagonist. In yet anotherembodiment the absence of SNP rs28373064 in combination with the absenceof SNP rs13099050, SNP rs7441352 and SNP rs12424153 is indicative for atreatment response to a V_(1B) receptor antagonist. In one embodiment,the presence of SNP rs28373064 in combination with the presence of SNPrs9880583, SNP rs730258, SNP rs12654236, SNP rs17091872, SNP rs12254219,SNP rs11575663, SNP rs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162and SNP rs8088242 and the absence of SNP rs28373064 in combination withthe absence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 isindicative for a treatment response to a V_(1B) receptor antagonist. Itis however to be understood that the analysis of other factors, such asthe gender of the patient and the presence or absence of each of theSNPs defined in Table 1 may further add to the prediction analysis forthe treatment response to a V_(1B) receptor antagonist.

A person skilled in the art can derive the exact position, nucleotidesequence, and indicator sequence from the above identifiedrs-nomenclature, e.g. from suitable database entries and associatedinformation systems, e.g. the Single Nucleotide Polymorphism database(dbSNP) which is incorporated herein by reference. The information mayalso be retrievable in case of changes to the nomenclature, or to thesurrounding sequence elements, e.g. based on history functions of asuitable database.

The term “determining the presence or absence of a biomarker” or“determining the presence or absence of a polymorphic variant” as usedherein refers to any suitable method or technique of detecting theidentity of an SNP, e.g. at the positions of the biomarkers describedherein. The determination method may be a sequencing technique or atechnique based on complementary nucleic acid binding. The context ofthe indicated positions, as well as the strand may differ, e.g. frompatient to patient, or from sample to sample etc.

Vasopressin receptor 1B (V_(1B)) antagonist as used herein refers to anycompound capable of binding directly or indirectly to a V_(1B) receptorso as to modulate the receptor mediated activity. Vasopressin receptor1B (V_(1B)) antagonists as used herein include V_(1B) receptorantagonists which were tested in clinical trials as well as V_(1B)receptor antagonists which are currently tested in clinical trials oralready admitted to the market. Various V_(1B) receptor antagonists havebeen described in the literature and tested in clinical trials.Exemplary V_(1B) receptor antagonists that have been tested in clinicaltrials comprise SSR149415 (also denoted as Nelivaptan; Sanofi-Aventis),Org 52186 (Organon), ABT-436 (Abbott) and ABT-558 (Abbott).

One embodiment of the present invention relates to a V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/orcopeptin level, wherein the V_(1B) receptor antagonist is selected fromthe group consisting of SSR149415, Org 52186, ABT-436 and/or ABT 558. Insome embodiments, a combination of any of the aforementioned V_(1B)receptor antagonists may be used for treatment of depressive and/oranxiety symptoms in a patient showing an elevated AVP level and/orcopeptin levels. In other embodiments, a compound selected from thegroup consisting of SSR149415, Org 52186, ABT-436 and/or ABT 558 may beused in combination with a further V_(1B) receptor antagonist as definedherein for the treatment of depressive symptoms and/or anxiety symptomsin a patient showing an elevated AVP level and/or an elevated copeptinlevel. In a specific embodiment the present invention relates to aV_(1B) receptor antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated AVPlevel and/or copeptin level, wherein the V_(1B) receptor antagonist isSSR149415. The V_(1B) receptor antagonist SSR149415 (also denoted asNelivaptan) developed by Sanofi-Aventis is a non-peptide V_(1B) receptorantagonist which is orally active (Serradeil-Le Gal et al. (2002);Characterization of (2S,4R)-1-(5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide (SSR149415), a Selective and Orally Active Vasopressine V_(1B) Receptor Antagonist; JPET 300:1122-1130). SSR149415 is a (2S,4R)-1-(5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamidehaving the structural formula

In another specific embodiment the present invention relates to a V_(1B)receptor antagonist for use in the treatment of depressive symptomsand/or anxiety symptoms in a patient showing an elevated AVP leveland/or copeptin level, wherein the V_(1B) antagonist is Org 52186. In afurther specific embodiment the present invention relates to a V_(1B)receptor antagonist for use in the treatment of depressive symptomsand/or anxiety symptoms in a patient showing an elevated AVP leveland/or copeptin level, wherein the V_(1B) receptor antagonist isABT-436. In another specific embodiment the present invention relates toa V_(1B) receptor antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated AVPlevel and/or copeptin level, wherein the V_(1B) receptor antagonist isABT-558.

In another embodiment of the invention, the patient showing an elevatedAVP level and/or an elevated copeptin level is treated withdexamethasone prior to the copeptin measurement or the measurement ofAVP. In another embodiment, the patient showing an elevated AVP leveland/or an elevated copeptin level is treated with dexamethasone prior tothe copeptin measurement and the measurement of AVP.

When one or more combined dexamethasone/corticotropin releasing hormonetest(s) (combined dex/CRH test) should subsequently be performed, theblood sample of the patient and/or the sample of the cerebrospinal fluidof the patient may be obtained after the patient has been treated withdexamethasone but before the patient has been treated with CRH.

The patient may be pre-treated with 0.5 mg to 3 mg of dexamethasone,optionally with 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5mg, 2.75 mg or 3 mg dexamethasone. In particular, the patient may bepre-treated with 1.5 mg dexamethasone. The blood sample and/or thesample of cerebrospinal fluid may be taken 12 to 36 hours after thepatient has been pre-treated with dexamethasone, optionally 15 to 24hours after the patient has been pre-treated with dexamethasone.

In addition to the copeptin measurement and/or the measurement of AVP,at least one, optionally two combined dexamethasone suppression CRHstimulation test(s) (dex/CRH test) may be performed. If more than onecombined dex/CRH test is performed, these tests are performed in certainintervals, e.g. intervals of days, weeks or months. Specifically, thecombined dex/CRH tests may be performed in an interval of about 30 orabout 60 days. It is however understood, that the length of the intervalmay be adapted by the person skilled in the art.

The combined dex/CRH test has been described by Heuser et al. (Thecombined dexamethasone/CRH test: a refined laboratory test forpsychiatric disorders., J Psychiatr Res, 1994, 28:341-356) and can beused for screening for compounds which may be useful in the treatment ofdepressive symptoms and/or anxiety symptoms. The dex/CRH test isdescribed further below with respect to the methods for predicting atreatment response to a V_(1B) receptor antagonist in a patient withdepressive symptoms and/or anxiety symptoms according to the inventionand it is understood that all aspects of said test as described beloware also relevant with respect to the combined dex/CRH test whenperformed in addition to the copeptin measurement and/or the measurementof AVP.

In another embodiment, the V_(1B) receptor antagonist for use in thetreatment of depressive syndromes and/or anxiety syndromes in a patientshowing an elevated arginine vasopressin (AVP) level and/or an elevatedcopeptin level is administered in combination with at least one furtherpharmaceutically active compound suitable for the treatment ofdepressive symptoms and/or anxiety symptoms. Pharmaceutically activecompounds which may be administered in combination with the V_(1B)receptor antagonist as described herein include in particular compoundslabeled for use in the treatment of depressive syndromes and/or anxietysyndromes, compounds currently studied in clinical trials for thetreatment of depressive symptoms and/or anxiety symptoms and/or anyother compound which is suitable for the treatment of depressivesymptoms and/or anxiety symptoms (e.g. use of known compounds notapproved by the competent agencies for the treatment of depressivesymptoms and/or anxiety symptoms but which are used off-label). It isunderstood within the meaning of the present invention that eachcompound mentioned herein may be used in combination with the V_(1B)receptor antagonist for use as described herein either alone or incombination with a further compound mentioned herein.

A non-exhaustive list of compounds suitable for the treatment ofdepressive symptoms and/or anxiety symptoms includes selective serotoninreuptake inhibitors, serotonin-norepinephrine reuptake inhibitors,dopamine reuptake inhibitors, noradrenergic and specific serotonergicantidepressants, norepinephrine (noradrenaline) reuptake inhibitors,selective serotonin reuptake enhancers, norepinephrine-dopaminedisinhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclicantidepressants, tetracyclic antidepressants, monamine oxidaseinhibitors, psychostimulants, mood stabilizers, amine precursors,serotonin antagonist and reuptake inhibitors, anticonvulsants, nicotine,phytopharmaceuticals, melatonin receptor antagonists, 5-HT antagonists,benzodiazepines, buspirone, azapirones, barbiturates, hydroxyzine,pregabalin, corticotropin-releasing hormone receptor antagonists,neurokinin receptor antagonists, oxytocin, glucocorticoid receptorantagonists.

Selective serotonin reuptake inhibitors (SSRIs) are compoundsspecifically blocking the transporter involved in the reuptake ofserotonin and constitute one of the most commonly used class ofantidepressants. Examples of SSRIs include citalopram, escitalopram,dapoxetine, fluoxetine, fluvoxamine, paroxetine, sertraline andvilazodone. In one embodiment of the invention the V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is used in combination withat least one SSRI which is optionally selected from the group consistingof citalopram, escitalopram, dapoxetine, fluoxetine, fluvoxamine,paroxetine, sertraline and vilazodone. The V_(1B) receptor antagonistfor use as described herein may be used in combination with one SSRI.Optionally, this SSRI is selected from the group consisting ofcitalopram, escitalopram, dapoxetine, fluoxetine, fluvoxamine,paroxetine, sertraline and vilazodone. In a specific embodiment, thepresent invention relates to SSR149415 for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level used in combinationwith at least one SSRI, which is optionally selected from the groupconsisting of citalopram, escitalopram, dapoxetine, fluoxetine,fluvoxamine, paroxetine, sertraline and vilazodone.

Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) exert theiractivity through blocking the norepinephrine transporter and may also beadministered in combination with the V_(1B) receptor antagonist for usedas described herein. NRIs as used herein also includes selectivenorepinephrine reuptake inhibitors as well as NRIs having ah activity ata different site. Exemplary NRIs are compounds such as atomoxetin,mazindol, reboxetine, esreboxetin, viloxazine, amedalin, daledalin,CP-39,332, edivoxtin, lortalamine, talopram, talsupram, tandamine,buproprion, ciclazindol and teniloxazine. In one embodiment of theinvention, the V_(1B) receptor antagonist for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level as described hereinis administered in combination with at least one norepinephrine reuptakeinhibitor, which is optionally selected from atomoxetin, mazindol,reboxetine, esreboxetin, viloxazine, amedalin, daledalin, CP-39,332,edivoxtin, lortalamine, talopram, talsupram, tandamine, buproprion,ciclazindol and teniloxazine. In a specific embodiment of the invention,the V_(1B) receptor antagonist for use as described herein administeredin combination with at least one norepinephrine reuptake inhibitor isSSR149415.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may also be usedfor the treatment of depressive symptoms and/or anxiety symptoms.Exemplary SNRIs are desvenlafaxine, duloxetine, milnacipran andvenlafaxine. In one embodiment of the invention, the V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is administered incombination with at least one SNRI, which is optionally selected fromthe group consisting of desvenlafaxine, duloxetine, milnacipran andvenlafaxine. In a specific embodiment of the invention, the V_(1B)receptor antagonist for use as described herein administered incombination with at least one SNRI is SSR149415.

Dopamine reuptake inhibitors (DRIs, DARIs) are compounds blocking theactivity of the dopamine transporter and include selective dopaminereuptake inhibitors as well as other DRIs. Examples of DRIs areamineptine, nomifensine, medifoxamine, methylphenidate, amfonelic acid,benzothiophenylcyclohexylpiperidine (BTCP), as well as Chaenomelesspeciosa. In one embodiment of the invention, the V_(1B) receptorantagonist for use in the treatment of depressive symptoms, and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is administered incombination with at least one DRI, which is optionally selected from thegroup consisting of amineptine, nomifensine, medifoxamine,methylphenidate, amfonelic acid, benzothiophenyl-cyclohexylpiperidine(BTCP), as well as Chaenomeles speciosa. In a specific embodiment of theinvention, the V_(1B) receptor antagonist for use as described hereinadministered in combination with at least one DRI is SSR149415.

Further compounds which may be administered in combination with theV_(1B) receptor antagonist for use as described herein are noradrenergicand specific serotonergic antidepressants (NaSSAs). Examples of NaSSAsinclude apitazapine, mianserin and mirtazepin. In one embodiment of theinvention the V_(1B) receptor antagonist for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level as described hereinis administered in combination with at least one NaSSA which isoptionally selected from the group consisting of aptazapine, mianserinand mirtazepin. In a specific embodiment of the invention, the V_(1B)receptor antagonist for use as described herein administered incombination with at least one NaSSA is SSR149415.

Selective serotonin reuptake enhances such as tianeptine may also beadministered in combination with the V_(1B) receptor antagonist for useas described herein. In a specific embodiment of the invention, theV_(1B) receptor antagonist for use as described herein is administeredin combination with at least one selective serotonin reuptake enhanceris SSR149415.

Norepinephrine-dopamine disinhibitors denotes a class of compoundsinhibiting the release of norepinephrine and dopamine such asagomelatine and may also be used in combination with the V_(1B) receptorantagonist for use as described herein. In a specific embodiment, theV_(1B) receptor antagonist for use as described herein administered incombination with at least one norepinephrine-dopamine disinhibitors isSSR149415.

Norepinephrine-dopamine reuptake inhibitors (NDRIs) are compoundsblocking the norepinephrine as well as the dopamine transporter.Exemplary NDRIs are bupropion, pipradrol, dexmethylphenidate, mesocarb,methylphenidatea and pyrovalerone. In one embodiment of the invention,the V_(1B) receptor antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated AVPlevel and/or an elevated copeptin level as described herein isadministered in combination with at least one NDRI, which is optionallyselected from the group consisting of bupropion, pipradrol,dexmethylphenidate, mesocarb, methylphenidatea and pyrovalerone. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with at least oneNDRI is SSR149415.

Tricyclic antidepressants (TCAs) are cyclic or heterocyclic chemicalcompounds having three cycles which are useful in the treatment ofdepressive symptoms and/or anxiety symptoms. Examples of tricylicantidepressants are amineptine, amitriptyline, amytriptylinoxide,butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin,dimetacrine, dosulepin, doxepin, imipramine, imipraminoxide, iprindole,lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline,noxiptiline, opipramol, pipofezine, propizepine, protriptyline,quinupramine, tianeptine and trimipramine. In one embodiment of theinvention, the V_(1B) receptor antagonist for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level as described hereinis administered in combination with at least one TCA, which isoptionally selected from the group consisting of amineptine,amitriptyline, amytriptylinoxide, butriptyline, clomipramine,demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepiri,doxcpin, imipramine, imipraminoxide, iprindole, lofepramine, melitracen,metapramine, nitroxazepine, nortriptyline, noxiptiline, opipramol,pipofezine, propizepine, protriptyline, quinupramine, tianeptine andtrimipramine. In a specific embodiment of the invention, the V_(1B)receptor antagonist for use as described herein administered incombination with at least one TCA is SSR149415.

The tetracyclic antidepressants (TeCAs) are also characterized by theirchemical structure and are cyclic or heterocyclic compounds having fourrings. TeCAs include compounds such as amoxapine, aptazapine,ciclazindol, maprotiline, mianserin, mirtazepine, oxaprotiline andsetiptiline. In one embodiment of the invention, the V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is administered incombination with at least one TeCA, which is optionally selected fromthe group consisting of amoxapine, aptazapine, ciclazindol, maprotiline,mianserin, mirtazepine, oxaprotiline and setiptiline. In a specificembodiment of the invention, the V_(1B) receptor antagonist for use asdescribed herein administered in combination with at least one TeCA isSSR149415.

Monoamine oxidase inhibitors (MAOIs) denote compounds blocking thedegradation of amines by inhibiting the activity of the enzyme monoamineoxidase. As used herein, MAOIs includes irreversible, reversible andpseudo-irreversible MAOIs as well as compounds selectively inhibitingeither monoamine oxidase type A (MAO-A) or monoamine oxidase type B(MAO-B) or showing a non-selective inhibition of MAO. Examplary MAOIsinclude isocaboxazid, moclobemide, phenelzine, selegiline andtranylcypromine. In one embodiment of the invention, the V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is administered incombination with at least one MAOI, which is optionally selected fromthe group consisting of isocaboxazid, moclobemide, phenelzine,selegiline and tranylcypromine. In a specific embodiment of theinvention, the V_(1B) receptor antagonist for use as described hereinadministered in combination with at least one MAOI is SSR149415.

As used herein, psychostimulants includes any compound which actsstimulating on a body e.g. by improving the mental and/or physicalfunction of the body. Exemplary types of psychostimulants includexanthines, piperazine derivatives and amphetamine derivatives (such asmethylphenidate). In one embodiment of the invention, the V_(1B)receptor antagonist for use in the treatment of depressive symptomsand/or anxiety symptoms in a patient showing ah elevated AVP leveland/or an elevated copeptin level as described herein is administered incombination with at least one psychostimulant, which is optionallyselected from the group consisting of xanthines, piperazine derivativesand amphetamine derivatives. In a specific embodiment of the invention,the V_(1B) receptor antagonist for use as described herein administeredin combination with at least one psychostimulant is SSR149415.

Mood stabilizers which can be used in combination with the V_(1B)receptor antagonist for use as described herein are any compound usefulfor treatment fast and unstable mood changes. Examples of moodstabilizers include lithium, valproic acid, carbamazepine, lamotrigine,oxacabezipine, riluzole and gabapentin. In one embodiment of theinvention, the V_(1B) receptor antagonist for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level as described hereinis administered in combination with at least one mood stabilizer, whichis optionally selected from the group consisting of lithium, valproicacid, carbamazepine, lamotrigine, oxacabezipine, riluzole andgabapentin. In a specific embodiment of the invention, the V_(1B)receptor antagonist for use as described herein administered incombination with at least one mood stabilizer is SSR149415.

Further compounds which may be administered in combination with theV_(1B) receptor antagonist for use as described herein are amineprecursors, i.e. metabolic precursors of monoamine neurotransmitter(such as dopamine, noradrenaline, serotonin and acetylcholine).Precursors of monoamine neurotransmitters include L-tryptophan,phenylalanine, 5-hydroxytryptophan, dopamine, L-tyrosine, cholin andL-DOPA. In one embodiment of the invention, the V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is administered incombination with at least one amine precursor, which is optionallyselected from the group consisting of L-tryptophan, phenylalanine,5-hydroxytryptophan, dopamine, L-tyrosine, cholin and L-DOPA. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with at least oneamine precursor is SSR149415.

Serotonin antagonists and reuptake inhibitors (SARIs) exert theiractivity by antagonizing serotonin receptors and include compounds suchas nefazodon, etoperidone, lorpiprazole, lubazodone, trazodone andmepiprazole. In one embodiment of the invention, the V_(1B) receptorantagonist for use in the treatment of depressive symptoms and/oranxiety symptoms in a patient showing an elevated AVP level and/or anelevated copeptin level as described herein is administered incombination with at least one SARI, which is optionally selected fromthe group consisting of nefazodon, etoperidone, lorpiprazole,lubazodone, trazodone and mepiprazole. In a specific embodiment of theinvention, the V_(1B) receptor antagonist for use as described hereinadministered in combination with at least one SARI is SSR149415.

Anticonvulsant as used herein relates to any compound useful in thetreatment and/or prevention of seizures, such as barbiturates,benzodiazepines, carboxamides, valproic acid and hydantoin derivatives.In one embodiment Of the invention, the V_(1B) receptor antagonist foruse in the treatment of depressive symptoms and/or anxiety symptoms in apatient showing an elevated AVP level and/or an elevated copeptin levelas described herein is administered in combination with at least oneanticonvulsant, which is optionally selected from the group consistingof barbiturates, benzodiazepines, carboxamides, valproic acid andhydantoin derivatives. In a specific embodiment of the invention, theV_(1B) receptor antagonist for use as described herein administered incombination with at least one anticonvulsant is SSR149415.

In one embodiment of the invention, the V_(1B) receptor antagonist foruse in the treatment of depressive symptoms and/or anxiety symptoms in apatient showing an elevated AVP level and/or an elevated copeptin levelas described herein is administered in combination with nicotine. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with nicotine isSSR149415.

Phytopharmaceuticals as used herein includes any composition wherein theactive ingredients are solely derived from plants (e.g. from SaintJohn's wort) and which are useful in the treatment of depressivesymptoms and/or anxiety symptoms. In one embodiment of the invention,the V_(1B) receptor antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated AVPlevel and/or an elevated copeptin level as described herein isadministered in combination with at least one phytopharmaceutical. In aspecific, embodiment of the invention, the V_(1B) receptor antagonistfor use as described herein administered in combination with at leastone phytopharmaceutical is SSR149415.

Compounds useful in the treatment of anxiety symptoms (so-calledanxiolytics) include e.g. benzodiazepines, azapirones, barbiturates,pregabalin, hydroxyzine and buspirone. In one embodiment of theinvention, the V_(1B) receptor antagonist for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level as described hereinis administered in combination with at least one anxiolytic, which isoptionally selected from the group consisting of benzodiazepines,azapirones, barbiturates, pregabalin, hydroxyzine and buspirone. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with at least oneanxiolytic is SSR149415.

Further compounds which may be administered in combination with theV_(1B) receptor antagonist for use as described herein include furtherreceptor antagonists such as 5-HT receptor antagonists, melatoninreceptor antagonists, corticotropin-releasing hormone (CRH) receptorantagonists, neurokinin receptor antagonists and glucocorticoid receptorantagonists. Optionally, corticotropin-releasing hormone (CRH) receptor,antagonists, neurokinin receptor antagonists and glucocorticoid receptorantagonists are administered in combination with the V_(1B) receptorantagonist for use as described herein.

5-HT (5-hydroxytryptamine, serotonin) receptor antagonists as usedherein refer to any compound capable of binding directly or indirectlyto a 5-HT receptor so as to modulate the receptor mediated activity.Several 5-HT receptor families, i.e. the 5-HT₁ receptor family, 5-HT₂receptor family, 5-HT₃ receptor family, 5-HT₄ receptor family, 5-HT₅receptor family, 5-HT₆ receptor family and 5-HT₇ receptor family areknown in the art, which may be further subdivided in various subtypes.The 5-HT receptor antagonists as used herein may be directed against anyof the aforementioned 5-HT receptor families and against any knownsubtype of these families, in particular against the 5-HT₂ family,specifically against the 5-HT_(2A), 5-HT_(2B) and/or 5-HT_(2C) subtype.Exemplary 5-HT receptor antagonists include azapirones (5-HT_(1A) and5-HT_(2A) receptor antagonists), aripiprazole (5-HT_(2A)) and agomelatin(5-HT_(2C) receptor antagonists). In one embodiment of the invention,the V_(1B) receptor antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated AVPlevel and/or an elevated copeptin level as described herein isadministered in combination with at least one 5-HT receptor antagonist,which is optionally selected from the group consisting of antagonistsagainst the 5-HT₁ receptor family, the 5-HT₂ receptor family, the 5-HT₃receptor family, the 5-HT₄ receptor family, the 5-HT₅ receptor family,the 5-HT₆ receptor family and the 5-HT₇ receptor family. In a specificembodiment of the invention, the V_(1B) receptor antagonist for use asdescribed herein administered in combination with at least one 5-HTreceptor antagonist is SSR149415. In a specific embodiment of theinvention, the V_(1B) receptor antagonist for use as described hereinadministered in combination with at least one 5-HT receptor antagonistselected from the group consisting of antagonists against a receptor ofthe 5-HT₁ receptor family, the 5-HT₂ receptor family, the 5-HT₃ receptorfamily, the 5-HT₄ receptor family, the 5-HT₅ receptor family, the 5-HT₆receptor family and the 5-HT₇ receptor family is SSR149415.

Melatonin receptor antagonists as used herein refer to any compoundcapable of binding directly or indirectly to the melatonin receptor soas to modulate the receptor mediated activity. An example of a melatoninreceptor antagonist is the melatonergic antidepressant agomelatine. Inone embodiment of the invention, the V_(1B) receptor antagonist for usein the treatment of depressive symptoms and/or anxiety symptoms in apatient showing an elevated AVP level and/or an elevated copeptin levelas described herein is administered in combination with at least onemelatonin receptor antagonist, which is optionally agomelatine. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with at least onemelatonin receptor antagonist is SSR149415.

CRH receptor antagonists as used herein refers to any compound capableof binding directly or indirectly to a CRH receptor 1 or a CRH receptor2 so as to modulate the receptor mediated activity. CRHR1 antagonistsare well known in the literature and are e.g. described in WO 94/13676,EP 0 773 023, WO 2004/047866, WO 2004/094420, WO 98/03510, WO 97/029109,WO 2006/044958, WO 2001/005776 and WO 95/033750. Exemplary CRHR1antagonists comprise NBI30775/R121919 (Neurocrine), CP316.311 (Pfizer),CP 154,526 (Pfizer), Emicerfont (Glaxo), ONO-2333Ms (OnoPharmaceutical), Pexacerfont (Bristol-Myers-Squibb), SSR125543(Sanofi-Aventis), NBI-34101 (Neurocrine) and TAI041 (Taisho). In oneembodiment of the invention, the V_(1B) receptor antagonist for use inthe treatment of depressive symptoms and/or anxiety symptoms in apatient showing an elevated AVP level and/or an elevated copeptin levelas described herein is administered in combination with at least one CRHreceptor antagonist, particularly a CRHR1 antagonist, which isoptionally selected from the group consisting of NBI30775/R121919,CP316.311, CP154,526, Emicerfont, ONO-2333Ms, Pexacerfont, SSR125543,NBI-34101 and TAI041. In another embodiment of the invention, the V_(1B)receptor antagonist for use in the treatment of depressive symptomsand/or anxiety symptoms in a patient showing an elevated AVP leveland/or an elevated copeptin level as described herein is administered incombination with at least one CRHR2 receptor antagonist. In a specificembodiment of the invention, the V_(1B) receptor antagonist for use asdescribed herein administered in combination with at least one CRHreceptor antagonist is SSR149415.

Neurokinin (NK) receptor antagonists (also known as tachykinin receptorantagonists) as used herein refers to any compound capable of bindingdirectly or indirectly to a neurokinin receptor (e.g. NK₁, NK₂ or NK₃)so as to modulate the receptor mediated activity. In particular, the NKreceptor antagonists are NK₁ receptor antagonists. Exemplary NK receptorantagonists are the NK₁ receptor antagonists vestipitant, L-733,060,Orveptitan, AV608, LY686017, 6R205171, L759274, CPR2721, Casopitant,Aprepitant, the NK₂ receptor antagonist saredutant and the NK₃ receptorantagonists osanetant and talnetant. In one embodiment of the invention,the V_(1B) receptor antagonist for use in the treatment of depressivesymptoms and/or anxiety symptoms in a patient showing an elevated AVPlevel and/or an elevated copeptin level as described herein isadministered in combination with at least one NK receptor antagonist,which is optionally selected from the group consisting of vestipitant,L-733,060, Orveptitan, AV608, LY686017, 6R205171, L759274, CPR2721,Casopitant, Aprepitant, saredutant, osanetant and talnetant. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with at least one NKreceptor antagonist, optionally in combination with at least one NK₁receptor antagonist is SSR149415.

Glucocorticoid receptor antagonists as used herein refers to anycompound capable of binding directly or indirectly to a glucocorticoidreceptor so as to modulate the receptor mediated activity such as thecompounds RU-43044 and RU 38486 (mifepristone). In one embodiment of theinvention, the V_(1B) receptor Antagonist for use in the treatment ofdepressive symptoms and/or anxiety symptoms in a patient showing anelevated AVP level and/or an elevated copeptin level as described hereinis administered in combination with at least one glucocorticoid receptorantagonist, which is optionally selected from the group consisting ofRU-43044 and RU 38486 (mifepristone). In a specific embodiment of theinvention, the V_(1B) receptor antagonist for use as described hereinadministered in combination with at least one glucocorticoid receptorantagonist is SSR149415.

In one embodiment of the invention, the V_(1B) receptor antagonist foruse in the treatment of depressive symptoms and/or anxiety symptoms in apatient showing an elevated AVP level and/or an elevated copeptin levelas described herein is administered in combination with oxytocin. In aspecific embodiment of the invention, the V_(1B) receptor antagonist foruse as described herein administered in combination with oxytocin isSSR149415.

The V_(1B) receptor antagonist for use as described herein and the atleast one further pharmaceutically active compound may be administeredat the same time or at different time points. The V_(1B) receptorantagonist for use as described herein may be administered first,followed by the administration of the at least one pharmaceuticallyactive compound mentioned herein or vice versa. Any sequence ofadministration of the V_(1B) receptor antagonist for use as describedherein and the at least one further pharmaceutically active compound isencompassed in the present invention, e.g. the V_(1B) receptorantagonist for use as described herein may also be administered inbetween two further pharmaceutically active compounds.

In another embodiment of the use of the V_(1B) receptor antagonist asdescribed herein, a patient showing an elevated AVP level and/or anelevated copeptin level is identified by (i) determining in a patient'ssample the status of a biomarker or a group of biomarkers as describedherein; and (ii) identifying the patient as eligible for a therapy witha V_(1B) receptor antagonist where the patient's sample is classified asshowing the presence or absence of indicator nucleotides as definedherein below.

In another embodiment, a patient showing an elevated AVP level and/or anelevated copeptin level is identified by predicting the patient'streatment response to the V_(1B) receptor antagonist by the predictionmethods as described herein below.

In particular, a further aspect of the present invention relates to amethod for predicting a treatment response to a V_(1B) receptorantagonist in a patient with depressive symptoms and/or anxietysymptoms, comprising the following steps:

-   (i) determining the presence or absence of at least one polymorphic    variant in the AVPR1B gene in a nucleic acid sample of said patient    and-   (ii) determining the presence or absence of at least one polymorphic    variant in the patient's genome excluding the AVPR1B gene in a    nucleic acid sample of said patient,    wherein the combination of the presence or absence of at least one    polymorphic variant in the AVPR1B gene with the presence or absence    of at least one polymorphic variant in the patient's genome    excluding the AVPR1B gene is indicative for the treatment response.

The polymorphic variant in the AVPR1B gene and/or in the patient'sgenome excluding the AVPR1B gene may be a single nucleotide polymorphism(SNP).

The term “determining the presence or absence of a biomarker” or“determining the presence or absence of a polymorphic variant in theAVPR1B gene” or “determining the presence or absence of a polymorphicvariant in the patient's genome excluding the AVPR1B gene” as usedherein refers to any suitable method or technique of detecting theidentity of an SNP, e.g. at the positions of the biomarkers describedherein in a sample derived from the patient. The determination methodmay be a sequencing technique or a technique based on complementarynucleic acid binding. The context of the indicated positions, as well asthe strand may differ, e.g. from patient to patient, or from sample tosample etc.

A “nucleic acid sample” or “patient's sample” as used herein may be anysample derived from any suitable part or portion of a subject's bodysuch as a blood sample, a hair sample, a skin sample or a saliva sampleof the patient from which nucleic acids can be extracted. In someembodiments, blood or saliva samples are used. The sample used in thecontext of the present invention for detecting the presence of apolymorphic variant or an SNP should be collected in a clinicallyacceptable manner, in particular in a way that nucleic acids and/orproteins arc preserved. Usually, nucleic acid or DNA is extracted orisolated or purified from the sample prior to determining the presenceor absence of the polymorphic variants described herein, e.g. inTable 1. Any method known in the art may be used for nucleic acid or DNAextraction or isolation or purification. Suitable methods comprise interalia steps such as centrifugation steps, precipitation steps,chromatography steps, dialyzing steps, heating steps, cooling stepsand/or denaturation steps.

In a specific embodiment of the method described herein, the polymorphicvariant in the AVPR1B gene for which the presence or absence isdetermined is SNP rs28373064 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 2, wherein in one or twoalleles of the wild-type nucleotide A is replaced by indicatornucleotide G.

In one embodiment of the invention, the at least one polymorphic variantin the patient's genome excluding the AVPR1B gene for which the presenceor absence is determined is selected from the group of biomarkerscomprising:

-   -   SNP rs9880583 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 3, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide G,    -   SNP rs13099050 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 4, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide C,    -   SNP rs7441352 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 5, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs730258 which is represented by a single polymorphic change        at position 27 of SEQ ID NO: 6, wherein in one or two alleles        the wild-type nucleotide C is replaced by indicator nucleotide        T,    -   SNP rs12654236 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 7, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs17091872 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 8, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs12254219 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 9, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs11575663 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 10, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs7080276 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 11, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G,    -   SNP rs7416 which is represented by a single polymorphic change        at position 27 of SEQ ID NO: 12, wherein in one or two alleles        the wild-type nucleotide A is replaced by indicator nucleotide        G,    -   SNP rs12424513 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 13, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs1035050 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 14, wherein in one or two        alleles the wild-type nucleotide C is replaced by indicator        nucleotide T,    -   SNP rs9959162 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 15, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide C, and/or    -   SNP rs8088242 which is represented by a single polymorphic        change at position 27 of SEQ ID NO: 16, wherein in one or two        alleles the wild-type nucleotide A is replaced by indicator        nucleotide G.

A further embodiment of the present invention relates to the methoddescribed herein, wherein the at least one polymorphic variant in theAVPR1B gene and/or in the patient's genome excluding the AVPR1B gene forwhich the presence or absence is determined is selected from a set/groupof biomarkers comprising at least 2, at least 5, at least 8 or at least11 of the markers as defined in Table 1. In one embodiment, the at leastone polymorphic variant in the AVPR1B gene and/or in the patient'sgenome excluding the AVPR1B gene for which the presence or absence isdetermined is selected from a set or group of biomarkers consisting ofthe biomarkers as defined in Table 1.

In another embodiment, the combination of the presence or absence of SNPrs28373064 with the presence or absence of at least 1, at least 2, atleast 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, at least 10, at least 11, at least 12, at least 13 or at least14 polymorphic variants in the patient's genome excluding the AVPR1Bgene as defined in Table 1 (excluding SNP rs28373064) is determined.

In yet another embodiment, the presence of SNP rs28373064 in combinationwith the presence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNPrs17091872, SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416,SNP rs1035050, SNP rs9959162 and SNP rs8088242 is indicative for atreatment response to a V_(1B) receptor antagonist. In yet anotherembodiment the absence of SNP rs28373064 in combination with the absenceof SNP rs13099050, SNP rs7441352 and SNP rs12424153 is indicative for atreatment response to a V_(1B) receptor antagonist. In one embodiment,the presence of SNP rs28373064 in combination with the presence of SNPrs9880583, SNP rs730258, SNP rs12654236, SNP rs17091872, SNP rs12254219,SNP rs11575663, SNP rs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162and SNP rs8088242 and the absence of SNP rs28373064 in combination withthe absence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 isindicative for a treatment response to a V_(1B) receptor antagonist. Itis however to be understood that the analysis of other factors, such asthe gender of the patient and the presence or absence of each of theSNPs defined in Table 1 may further add to the prediction analysis forthe treatment response to a V_(1B) receptor antagonist.

It is understood that additionally the presence of one or more furthermarker(s), such as clinical markers may be determined in addition to thepresence of the herein-described markers. Such clinical markers mayinclude the AVP and/or copeptin level.

According to the method described herein, the presence or absence of thepolymorphic variant in the AVPR1B gene and the presence or absence ofthe one or more further markers may determined by single nucleotidepolymorphism genotyping analysis. The term “single nucleotidepolymorphism (SNP) genotyping analysis” as used herein refers to a testof determining in one or several patients the presence or absence of atleast one SNP, typically several SNPs, and in some embodiments all(known) SNPs the human genome, including endogenous and exogenousregions.

For example, the determination of the nucleotide sequence and/ormolecular structure may be carried out through allele-specificoligonucleotide (ASO)-dot blot analysis, primer extension assays, iPLEXSNP genotyping, Dynamic allele-specific hybridization (DASH) genotyping,the use of molecular beacons, tetra primer ARMS PCR, a flap endonucleaseinvader assay, an oligonucleotide ligase assay, PCR-single strandconformation polymorphism (SSCP) analysis, quantitative real-time PCRassay, SNP microarray based analysis, restriction enzyme fragment lengthpolymorphism (RFLP) analysis, targeted resequencing analysis and/orwhole genome sequencing analysis.

SNP genotyping analysis can be performed by methods known in the artsuch as microarray analysis or sequencing analysis or PCR relatedmethods or mass spectrometry or 5′-nuclease assays or allele specifichybridization or high-throughput variants of these techniques orcombinations thereof. These and other methods are known in the art. Seefor example Rampal, DNA Arrays: Methods and Protocols (Methods inMolecular Biology) 2010; Graham & Hill, DNA Sequencing Protocols(Methods in Molecular Biology) 2001; Schuster, Nat. Methods, 2008 andBrenner, Nat. Biotech., 2000; Mardis, Annu Rev Genomics Hum Genet.,2008. Genomewide arrays can be purchased from different suppliers suchas Illumia and Affymetix.

In another embodiment of the present invention, a patient showing anelevated AVP level and/or an elevated copeptin level can be identifiedby (i) determining in a patient's sample the status of a biomarker or agroup of biomarkers as defined above; and (ii) identifying the patientas eligible for a therapy with a V_(1B) receptor antagonist, where thealgorithm provided by the method described below predicts that thepatient responds to the treatment with V_(1B) receptor antagonist.

One aspect of the invention thus concerns the provision of such analgorithm for predicting a treatment response to V_(1B) receptorantagonists in patients with depressive symptoms and/or anxietysymptoms. The method may comprise the following steps:

-   (a) performing a single nucleotide polymorphism (SNP) genotyping    analysis in a group of patients with depressive symptoms and/or    anxiety symptoms;-   (b) determining a value indicative for CRH activity in each patient    of the group, wherein a value indicative for CRH overactivity is    indicative or predictive for a patient responding,to a treatment    with a V_(1B) receptor antagonist;-   (c) determining whether the presence or absence of at least one SNP    and combination of the presence or absence of at least two SNPs is    associated with a value indicative for CRH overactivity as    determined in step (b);-   (d) determining the algorithm by machine-learning from the    association of the at least one SNP identified in step (c) with the    value indicative for CRH overactivity and the association of the    interactions of at least two SNPs identified in step (c) with a    value indicative for CRH overactivity.

In a step (a), a single nucleotide polymorphism (SNP) genotypinganalysis in a group of patients with depressive symptoms and/or anxietysymptoms is performed.

A “group of patients” as used herein comprises at least two patients,such as at least 10 patients, or at least 100 patients, or at least 150patients. Patients included in the analysis of step (a) may exhibit atleast a moderate to severe depressive mode. The group of patients maycomprise patients with CRH overactivity and/or patients with normal CRHactivity.

SNP genotyping analysis can be performed by methods known in the artsuch as the methods mentioned herein.

In some embodiments, any of the methods described herein comprises thedetermination of the haplotype for two copies of the chromosomecomprising the SNPs identified herein.

Typically, a SNP is considered in the genotyping analysis if it occursin a certain percentage in the population, for example in at least 5% orat least 10% of the population. In other words, the minor allelefrequency (MAF) is larger than 0.05 or 0.10 (MAF>0.05 or MAF>0.10).

For the SNP genotyping analysis a nucleic acid or DNA sample from apatient may be used. The nucleic acid or DNA sample can be a bloodsample, a hair sample, a skin sample or a salvia sample of the patient.Any other sample obtainable from the patient and containing patientnucleic acid or DNA can also be used. The sample can be collected fromthe patient by any method known in the art. For example, a blood samplecan be taken from a patient by use of a sterile needle. The collectionof salvia out of the mouth and throat of the patient can be performed byuse of a sterile cotton bud or by flushing said area and collecting theflushing solution.

Usually, the nucleic acid or DNA is extracted or isolated or purifiedfrom the sample prior to SNP genotyping analysis. Any method known inthe art may be used for nucleic acid or DNA extraction or isolation orpurification. Suitable methods comprise inter alia steps such ascentrifugation steps, precipitation steps, chromatography steps,dialyzing steps, heating steps, cooling steps and/or denaturation steps.For some embodiments, a certain nucleic acid or DNA content in thesample may be reached. Nucleic acid or DNA content can be measured forexample via UV spectrometry as described in the literature. However, inalternative embodiments SNP genotyping analysis may also be performed byusing a non-extracted or non-purified sample.

Nucleic acid or DNA amplification may also be useful prior to the SNPanalysis step. Any method known in the art can be used for nucleic acidor DNA amplification. The sample can thus be provided in a concentrationand solution appropriate for the SNP analysis.

The analyzed SNPs may be represented by values 0, 1 or 2. The value “0”may indicate that the SNP is present on none of the two homologouschromosomes. The value “1” may indicate that the SNP is present oh oneof the two homologous chromosomes. The value “2” may indicate that theSNP is present on both homologous chromosomes. Homologous chromosomescorrespond to each other in terms of chromosome length, gene loci andstaining pattern. One is inherited from the mother, the other from thefather.

In a step (b) of the method for providing a prediction algorithm, avalue indicative for CRH activity in each patient is determined.

A “value indicative for CRH activity”, a “value indicative for CRHoveractivity” and/or a “value indicative for normal CRH activity” can beobtained by determining the concentration or activity of CRH and/or of adownstream target of the CRHR1 receptor. The analysis is usually set upin a way that it can be excluded that the modulation of activity orconcentration of a downstream target of the CRHR1 receptor is due toanother disturbance than CRH activity. For instance, the concentrationsor activities of adrenocorticotrophin (ACTH) and/or cortisol are usefulbiomarkers for determining a value indicative for CRH overactivity.Typically, the CRH overactivity in each patient may be determined bymeasuring the ACTH and/or cortisol level response to a combineddexamethasone suppression/CRH stimulation test as described herein.

Steps (c) and (d) of the method for providing a prediction algorithm mayanalyze the association of the analyzed SNPs with the value indicativefor CRH overactivity and/or normal CRH activity and generate analgorithm for predicting the treatment response to V_(1B) receptorantagonists. In addition or alternatively, steps (c) and (d) of themethod for providing a prediction algorithm may analyze the associationof a combination of the presence or absence of at least two of theanalyzed SNPs, in particular a combination of the presence or absence ofat least one SNP in the AVPR1B gene with the presence or absence of atleast one SNP in the genome of the patient excluding the AVPR1B genewith a value indicative for CRH overactivity and/or normal CRH activityand generate an algorithm for predicting the treatment response toV_(1B) receptor antagonists. Additionally, steps (c) and (d) of themethod for providing a prediction algorithm may analyze the associationof the gender of the patient from which the sample was derived with avalue indicative for CRH overactivity and/or normal CRH activity andgenerate an algorithm for predicting the treatment response to V_(1B)receptor antagonists.

In an exemplary embodiment, the group of patients may be split into twosets of similar size and similar values for descriptors such asdemographic descriptors or clinical descriptors. These two sets arehereinafter also referred to as “training set” and “test set”.

In step (c) of the method of this exemplary embodiment, at least one SNPassociated with the value indicative for CRH overactivity and/or normalCRH activity as determined in step (b) is identified in the trainingset. In addition or alternatively, in step (c) the association of acombination of the analyzed SNPs with a value indicative for CRHoveractivity and/or normal CRH activity as determined in step (b) may beidentified in the training set. Optionally, in step (c) the associationof the gender of the patient from which the sample was derived with avalue indicative for CRH overactivity and/or normal CRH activity asdetermined in step (b) is identified in the training set.

Further, there can be at least two alternatives for the result providedby the prediction algorithm. First, the result may be a categoricalanswer whether the patient responds to V_(1B) receptor antagonisttreatment or not. Second, the prediction algorithm may provide theanswer to which degree the patient responds or docs not respond to thetreatment. Depending on the desired result provided by the predictionalgorithm the way of determining the algorithm may differ.

In the alternative the prediction algorithm will analyze whether apatient responds or does not respond to V_(1B) receptor antagonisttreatment, the values indicative for CRH activity may be provided aslogic data variable (Boolean type; 0 vs. 1; true vs. false, high vs. lowresponder). Therefore, if the test performed to determine valuesindicative for CRH overactivity provides a data range, the patients maybe dichotomized by a threshold into high vs. low responders.

In the alternative the test will analyze to which degree or likelihoodthe patient may respond or may not respond to V_(1B) receptor antagonisttreatment, the values indicative for CRH activity may be provided asnumerical values.

Typically, SNPs that are modified in a significant percentage of thepopulation are used in the method for providing a prediction algorithm.For example, only SNPs with a minor allele frequency (MAF) greater than0.05 or 0.10 may be selected for further analysis. This means that onlySNPs that are modified in at least 5% or 10% of the population areselected for further analysis.

Association for all SNPs or combinations of SNPs with the valueindicative for CRH activity is tested by an association analysis testingthe likelihood for a patient to be CRH overactive vs. CRH non-overactivein dependence of the genotype of said patient. Said association analysismay be conducted for example by an additive genetic model and/or by alogistic regression. A SNP or combination of at least two SNPs is e.g.identified to be associated with a value indicative for CRH overactivityif the corresponding p-value is at least 1×10⁻³ or at least 1×10⁻⁴ or atleast 1×10⁻⁵. The lower the p-value the more the SNP is associated witha value indicative for CRH overactivity. Accordingly, an SNP orcombination of at least two SNPs is e.g. identified to be associatedwith a value indicative for normal CRH activity if the correspondingp-value is at least 1×10⁻³ or at least 1×10⁻⁴ or at least 1×10⁻⁵. In oneembodiment of the invention, only SNPs or combinations of SNPs with ap-value of <1×10⁻⁵ are used.

In step (d) of this exemplary embodiment, the algorithm for predicting atreatment response to V_(1B) receptor antagonist may be determined bythe use of SNPs or combinations of SNPs in the test set by a machinelearning method.

The term “algorithm for predicting” as used herein may refer to aclassification function (also known as binary classification test).

The term “machine-learning” as used herein may refer to a method knownto the person skilled in the art of machine learning. In particular,machine learning is concerned with the design and development ofalgorithms that allow computers to evolve behaviors based on empiricaldata, such as from sensor data or databases. It may be selected from thegroup consisting of artificial neural network learning, decision treelearning, support vector machine learning, Bayesian network learning,clustering, and regression analysis.

The term “reliable prediction of the treatment response to a V_(1B)receptor antagonist” as used herein may refer to a high performance ofthe prediction algorithm. The evaluation of the performance of theprediction algorithm may depend on the problem the algorithm is appliedfor. If the algorithm is used to identify patients that are likely toresponse to the treatment with V_(1B) receptor antagonists theperformance is usually expressed by a high accuracy and/or sensitivityand/or precision. If patients should be identified which are likely notto respond to the treatment with V_(1B) receptor antagonist, specificityand/or negative predictive value are typical statistical measures todescribe the performance of the prediction algorithm.

For optimizing the prediction performance of the algorithm, the step ofdetermining the algorithm by a machine-learning method in a first subsetof the test set and testing the prediction performance in an secondindependent subset of the test set may be repeated based on differentnumbers and groups of SNPs, until the desired prediction performance isreached.

Accuracy, sensitivity, precision, specificity and negative predictivevalue are exemplary statistical measure of the performance of theprediction algorithm. In the following, examples are given fordetermining the performance of the prediction algorithm.

As used herein, accuracy may be calculated as (number of truepositives+number of true negatives)/(number of true positives+number offalse positives+number of true negatives+number of false negatives),e.g. (number of patients correctly diagnosed as responding to V_(1B)receptor antagonist+number of patients correctly diagnosed as notresponding to V_(1B) receptor antagonist)/(number of patients correctlydiagnosed as responding to V_(1B) receptor antagonist+number of patientswrongly diagnosed as responding to V_(1B) receptor antagonist+number ofpatients correctly diagnosed as not responding to V_(1B) receptorantagonist+number of patients wrongly diagnosed as not responding toV_(1B) receptor antagonist). The accuracy of prediction may e.g. be atleast 60%, at least 70%, at least 80% or at least 90%.

A used herein, sensitivity may be calculated as (true positives)/(truepositives+false negatives), e.g.: (number of patients correctlydiagnosed as responding to V_(1B) receptor antagonist)/(number ofpatients correctly diagnosed as responding to V_(1B) receptorantagonist+number of patients wrongly diagnosed as not responding toV_(1B) receptor antagonist). The sensitivity of prediction may be atleast 60%, at least 70%, at least 80% or at least 90%.

As used herein, precision (also referred to as positive predictivevalue) may be calculated as (true positives)/(true positives+falsepositives), e.g.: (number of patients correctly diagnosed as respondingto V_(1B) receptor antagonist)/(number of patients correctly diagnosedas responding to V_(1B) receptor antagonist+number of patients wronglydiagnosed as responding to V_(1B) receptor antagonist). The precision ofprediction may be at least 60%, at least 70%, at least 80% or at least90%.

As used herein, specificity is calculated as (true negatives)/(truenegatives+false positives), e.g.: (number of patients correctlydiagnosed as not responding to V_(1B) receptor antagonist)/(number ofpatients correctly diagnosed as not responding to V_(1B) receptorantagonist+number of patients wrongly diagnosed as responding to V_(1B)receptor antagonist). The specificity of prediction may be at least 60%,at least 70%, at least 80% or at least 90%.

As used herein, negative predictive value is calculated as (truenegatives)/(true negatives+false negatives), e.g.: (number of patientscorrectly diagnosed as not responding to V_(1B) receptorantagonist)/(number of patients correctly diagnosed as not responding toV_(1B) receptor antagonist+number of patients wrongly diagnosed as notresponding to V_(1B) receptor antagonist). The negative predictive valuemay be at least 60%, at least 70%, at least 80% or at least 90%.

Other statistical measures useful for describing the performance of theprediction algorithm are geometric mean of sensitivity and specificity,geometric mean of positive predictive value and negative predictivevalue, F-measure and area under ROC curve, and the positive and negativelikelihood ratios, the false discovery rate and Matthews correlationcoefficient. These measures and method for their determination are wellknown in the art.

In general, a prediction algorithm with high sensitivity may have lowspecificity and vice versa. The decision to select an algorithm havingcertain statistical characteristics such as accuracy, sensitivity orspecificity may also depend on the costs associated with a treatmentwith a V_(1B) receptor antagonist should the prediction be positiveand/or whether such a treatment is detrimental in cases where the resultis a false positive.

For a prediction whether a patient likely responds to the treatment withV_(1B) receptor antagonists the prediction algorithm may be based on anumber of SNPs and/or combinations of SNPs sufficient to achieve aprediction sensitivity and/or precision of at least 55%, optionally atleast 80%.

For the prediction whether it is unlikely that a patient responds to thetreatment with V_(1B) receptor antagonists the prediction algorithm maybe based on a number of SNPs and/or combinations of SNPs sufficient toachieve a prediction specificity and/or negative predictive value of atleast 55%, optionally at least 80%.

For a prediction whether a patient responds to a treatment with V_(1B)receptor antagonists or not the prediction algorithm may be based on anumber of SNPs and/or combinations of SNPs sufficient to achievesensitivity and/or precision and/or specificity and/or negativepredictive value of at least 55%, optionally at least 80%.

In one embodiment, a number N of SNPs and/or combinations of SNPs isassociated with a value indicative for CRH overactivity or normal CRHactivity in step (c) of the method for providing an algorithm, wherein Nis sufficient to provide an accuracy of at least 80% and a sensitivityof at least 70% and a specificity of at least 70%. In anotherembodiment, N is sufficient to provide an accuracy of at least 85% and asensitivity of at least 80% and a specificity of at least 80%. In oneembodiment, a sufficient number N of SNPs and/or combinations of SNPscomprises at least one polymorphic variant in the AVPR1B gene incombination with a set or group of polymorphic variants in the patient'sgenome excluding the AVPR1B gene, e.g. to a combination of a polymorphicvariant in the AVPR1B gene, optionally SNP rs28373064, with at least 1,at least 2, at least 3, at least 4, at least 5, at least 6, at least 7,at least 8, at least 9, at least 10, at least 11, at least 12, at least13, or at least 14 polymorphic variant(s) as described herein forpolymorphic variants in the patient's genome excluding the AVPR1B gene.

In another embodiment, the presence or absence of a number M of SNPsand/or combinations of SNPs is determined in step (a) of the method forpredicting a treatment response, wherein M is sufficient to provide anaccuracy of at least 80% and a sensitivity of at least 70% and aspecificity of at least 70%. In another embodiment, M is sufficient toprovide an accuracy of at least 85% and a sensitivity of at least 80%and a specificity of at least 80%. In one embodiment, a sufficientnumber M of SNPs and/or combinations of SNPs comprises at least onepolymorphic variant in the AVPR1B gene in combination with a set orgroup of polymorphic variants in the patient's genome excluding theAVPR1B gene, e.g. to a combination of a polymorphic variant in theAVPR1B gene, optionally SNP rs28373064, with at least 1, at least 2, atleast 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, at least 10, at least 11, at least 12, at least 13, or at least14 polymorphic variant(s) as described herein for polymorphic variantsin the patient's genome excluding the AVPR1B gene.

Typically, at least 2, at least 5, at least 8 or at least 11 SNPs and/orcombinations of SNPs are used for determination of the algorithm in step(d) of the method for providing a prediction algorithm.

The skilled person in the art knows that the use of differentmachine-learning methods and adapting parameters used therein can bealso used for improvement of the prediction reliability. The wholestatistical work-flow can be automated by a computer.

Thus, in one embodiment the method for predicting a treatment responseto a V_(1B) receptor antagonists further comprises a step (iii), whereinthe treatment response to V_(1B) receptor antagonists is predicted bylinking the algorithm provided by the method for providing a predictionalgorithm with the presence or absence of at least one SNP andcombination of SNPs as determined in step (i) and (ii) of said method.In particular, said SNPs correspond to the SNPs shown herein in Table 1and the combinations of SNPs described herein.

“Linking an algorithm for predicting a treatment response to V_(1B)receptor antagonist in patients having depressive symptoms and/oranxiety symptoms with the presence or absence of the at least one SNPand/or combination of SNPs” as used herein may refer to using such analgorithm to predict the treatment response based on the determinedpresence or absence of the at least one SNP and/or combination of SNPs,e.g. by integrating the at least one SNP and/or combination of SPCsdetermined in step (a) of the above method by the algorithm. In oneembodiment, the presence of SNP rs28373064 in combination with thepresence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNP rs17091872,SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416, SNPrs1035050, SNP rs9959162 and SNP rs8088242 may be integrated by thealgorithm. In another embodiment the absence of SNP rs28373064 incombination with the absence of SNP rs13099050, SNP rs7441352 and SNPrs12424153 may be integrated by the algorithm. In particular, thepresence of SNP rs28373064 in combination with the presence of SNPrs9880583, SNP rs730258, SNP rs12654236, SNP rs17091872, SNP rs12254219,SNP rs11575663, SNP rs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162and SNP rs8088242 and the absence of SNP rs28373064 in combination withthe absence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 may beintegrated by the algorithm. As already mentioned above, furtherfactors, such as the gender of the patient and the presence or absenceof the SNPs defined herein in Table 1 may also be integrated by thealgorithm.

Another aspect of the invention relates to a method for predicting atreatment response to a V_(1B) receptor antagonist in a patient withdepressive symptoms and/or anxiety symptoms, wherein the copeptinconcentration in a blood sample of said patient is determined and/or theAVP concentration in a sample of cerebrospinal fluid of said patient isdetermined and wherein an elevated copeptin and/or an elevated AVPconcentration is indicative for a patient responding to a treatment witha V_(1B) receptor antagonist.

In particular, another aspect of the present invention relates to amethod for predicting a treatment response to a V_(1B) receptorantagonist in a patient with depressive symptoms and/or anxietysymptoms, wherein the copeptin concentration in a blood sample of saidpatient is determined or the AVP concentration in a sample ofcerebrospinal fluid of said patient is determined and wherein thepresence of an elevated copeptin or an elevated AVP concentration isindicative for a patient responding to a treatment with a V_(1B)receptor antagonist.

Another aspect of the present invention relates to a method forpredicting a treatment response to a V_(1B) receptor antagonist in apatient with depressive symptoms and/or anxiety symptoms, wherein boththe copeptin concentration in a blood sample of said patient isdetermined and the AVP concentration in a sample of cerebrospinal fluidof said patient are determined and wherein the presence of both, anelevated copeptin and an elevated AVP concentration is indicative for apatient responding to a treatment with a V_(1B) receptor antagonist.

The patient may be a patient showing depressive symptoms. Alternatively,the patient may be a patient showing anxiety symptoms. Alternatively,the patient may be a patient showing both, depressive and anxietysymptoms.

The term “treatment response to a V_(1B) antagonist in patients withdepressive symptoms and/or anxiety symptoms” in the sense of theinvention refers to a response in a patient with depressive symptomsand/or anxiety symptoms during and/or after the treatment with one ormore V_(1B) antagonists compared to the state before the treatment. Theresponse may range from a partial alleviation of the symptoms to acomplete remission of the symptoms, indicated by the change of symptomsstrength and/or frequency of relapse of individual symptoms and/or themean change on a depression scale, e.g. as described herein. Theresponse can occur shortly after treatment or after a certain timeperiod. A decrease in symptom severity from pre-treatment of 25% or moreis usually considered a partial alleviation of symptoms. Remission maybe defined as achieving a value of 8 or less on the Hamilton DepressionRating Scale (HAM-D) or equivalent values on other rating scales namedherein.

The blood sample and the sample of cerebrospinal fluid can be obtainedfrom the patient by any method known in the art. For example, a bloodsample can be taken from a patient by use of a sterile needle and acerebrospinal fluid sample can be taken by lumbar juncture. It is alsounderstood that all steps necessary for preparing the sample for therespective measurement are also encompassed in the method according tothe invention. Such preparation steps include e.g. the preparation ofthe blood sample in order to obtain blood plasma as described above andare known to the person skilled in the art.

In a specific embodiment of the method described herein, the bloodsample of the patient and/or the sample of the cerebrospinal fluid ofthe patient is/are taken after the patient has been treated withdexamethasone. Subsequently, the copeptin concentration in the bloodsample and/or the AVP concentration in the sample of cerebrospinal fluidof said patient is/are determined.

When at least one combined dexamethasone/corticotropin releasing hormonetest (combined dex/CRH test) should subsequently be performed, the bloodsample of the patient and/or the sample of the cerebrospinal fluid ofthe patient may be obtained after the patient has been treated withdexamethasone but before said patient has been treated with CRH in thecourse of each combined dex/CRH test.

The patient may be pre-treated with 0.5 mg to 3 mg of dexamethasone,optionally with 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5mg, 2.75 mg or 3 mg dexamethasone. In particular, the patient may bepre-treated with 1.5 mg dexamethasone. The blood sample may be taken 12to 36 hours after the patient has been treated with dexamethasone,optionally 15 to 24 hours after the patient has been treated withdexamethasone.

In one embodiment of the method for predicting a treatment response to aV_(1B) receptor antagonist in a patient with depressive symptoms and/oranxiety symptoms as described herein the patient is additionallysubjected to at least one combined dexamethasone suppression CRHstimulation test (dex/CRH test). When more than one combined dex/CRHtest is performed, these tests are performed in certain intervals, e.g.intervals of days, weeks or months. Optionally, the patient is subjectedto at least one, particular two combined dex/CRH tests, whereby thetests are performed in an interval of about 30 days or of about 60 days.It is however understood that the length of the interval between thetests may be adapted as considered necessary by the person skilled inthe art.

The combined dex/CRH test has been described by Heuser et al. (Thecombined dexamethasone/CRH test: a refined laboratory test forpsychiatric disorders., J Psychiatr Res, 1994, 28:341-356) and can beused for screening for compounds which may be useful in the treatment ofdepressive symptoms and/or anxiety symptoms. In detail, in the combineddex/CRH test subjects arc pre-treated with dexamethasone (e.g. 1.5 mgdexamethasone) and blood is drawn in certain intervals after thedexamethasone treatment. This blood sample shows the suppression ofcortisol by dexamethasone. The pre-treatment is normally performed inthe evening prior to the day of the CRH administration. Human CRH (e.g.100 μg CRH) is administered after the first pre-treatment withdexamethasone, e.g. 16 hours after the pre-treatment. Subsequently,blood samples are drawn (e.g. in intervals of 15 minutes) from thepatient and the plasma ACTH and/or cortisol concentrations aredetermined. The neuroendocrine response to the dex/CRH test may beanalyzed using the total area under the curve (AUC) of the ACTHresponse. Patients suffering from depression normally show an increasedrelease of cortisol and of adrenocorticotropic hormone (ACTH) inresponse to the combined treatment with dexamethasone and CRH asperformed during the test, thus indicating a dysregulation of thehypothalamic-pituitary-adrenal (HPA) axis. Patients with a high HPA axisdysregulation show AUC values of cortisol of between 3000 and 18000 AUCunits (ng/ml×75 min) and/or AUC values of ACTH of between 1000 and 6500AUC units (pg/ml×75 min). Patients having a low HPA axis dysregulationshow AUC values of cortisol of between 300 and 2500 AUC units (ng/ml×75min) and/or AUC values of ACTH of between 250 and 1000 AUC units(pg/ml×75 min) Various antidepressants lead to a reduction of theseincreased cortisol and ACTH levels in a combined dex/CRH test performedafter the treatment with the antidepressants. Treatment response toantidepressants can thus be determined by performing a second dex/CRHtest after treatment with the antidepressant and comparing theneuroendocrine response to the one shown in a combined dex/CRH testperformed prior to treatment with the antidepressant.

In one embodiment of the present method for predicting a treatmentresponse to a V_(1B) receptor antagonist in a patient with depressivesymptoms and/or anxiety symptoms as described herein, an elevated AVPlevel in said patient is determined by means of AVP measurement in asample of cerebrospinal fluid of said patient. Samples of cerebrospinalfluid can be obtained from the patient by any method known in the art,e.g. by lumbar puncture.

Methods for determination of AVP levels in a sample of cerebrospinalfluid of a patient are known in the art and include immunoassays, e.g.radioimmunoassays. Hence, in another embodiment of the invention the AVPlevel in the sample of cerebrospinal fluid of the patient is measured bymeans of immunoassay, optionally by means of radioimmunoassay.

As used herein, an elevated AVP level denotes any AVP level higher thanthe AVP level measured in blood samples and/or samples of thecerebrospinal liquid of healthy individuals. Specifically, an elevatedAVP level in a patient showing depressive symptoms and/or anxietysymptoms is indicated by an AVP concentration in the sample ofcerebrospinal fluid of at least 4 pg/ml AVP, least 5 pg/ml AVP, least 6pg/ml AVP, least 7 pg/ml AVP, least 8 pg/ml AVP, at least 10 pg/ml AVP,at least 20 pg/ml AVP, at least 30 pg/ml AVP, at least 50 pg/ml AVP, atleast 70 pg/ml AVP or at least 90 pg/ml AVP. Elevated AVP levels may beindicated by an AVP concentration in the sample of cerebrospinal fluidin the range from 4 to 8 pg/ml AVP, optionally in the range from 4 to 6pg/ml AVP. Such elevated AVP concentrations are indicative for a patientresponding to a treatment with a V_(1B) receptor antagonist as describedherein.

In a further embodiment, the present invention relates to method forpredicting a treatment response to a V_(1B) receptor antagonist in apatient with depressive symptoms and/or anxiety symptoms as describedherein, wherein an elevated AVP level and/or an elevated copeptin levelin said patient is determined by means of copeptin measurement.

Methods for determination of copeptin levels in a blood sample derivedfrom a patient are known in the art and include immunoassays, e.g.sandwich immunoassays. Examples of such immunoassays are the CopeptinEIA Kit provided by BioSupply UK, the Thermo Scientific BRAHMS copeptinKryptor assay and the Thermo Scientific BRAHMS copeptin Kryptor us assayprovided by ThermoScientific.

Hence, in another embodiment of the method according to the invention,the AVP level and/or copeptin level of the patient showing depressivesymptoms and/or anxiety symptoms is determined by means of animmunoassay, optionally by means of a sandwich immunoassay. According tothe method of the invention, the copeptin level is determined in a bloodsample of the patient as defined herein. The blood sample can beobtained from the patient by any method known in the art, e.g. with asterile needle. In a specific embodiment of the invention, the copeptinlevel is determined in the blood plasma derived from the blood sample ofsaid patient. It is known in the art that blood plasma may be derived bycentrifugation of a blood sample to which an anti-coagulant has beenadded.

As used herein, an elevated copeptin level denotes any copeptin levelhigher than the copeptin level measured in blood samples of healthyindividuals. Specifically, an elevated copeptin level and therefore alsoan elevated AVP level in a patient showing depressive symptoms and/oranxiety symptoms is indicated by a copeptin blood concentration of atleast 5 pmol/L, at least 6 pmol/L, at least 7 pmol/L, at least 8 pmol/L,at least 9 pmol/L, at least 10 pmol/ml, at least 20 pmol/ml, at least 30pmol/ml, at least 40 pmol/ml, at least 50 pmol/ml, at least 60 pmol/ml,at least 70 pmol/ml, at least 80 pmol/ml, at least 90 pmol/ml or atleast 100 pmol/ml. Elevated copeptin levels and therefore also elevatedAVP levels may be indicated by a copeptin blood concentration in therange from 5 to 9 pmol/L, optionally in the range from 5 to 7 pmol/L.Such elevated copeptin levels are indicative for a patient responding toa treatment with a V_(1B) receptor antagonist as described herein.

It is also encompassed in the invention that both, the elevated copeptinlevel in a blood sample of the patient and the elevated AVP level in asample of cerebrospinal fluid of the patient is determined in thepatient by means of copeptin measurement and measurement of AVP in orderto predict the treatment response to a V_(1B) receptor antagonist.

The methods described above are not restricted to methods predicting atreatment response to V_(1B) antagonists in patients with depressivesymptoms and/or anxiety symptoms. The treatment response of patientswith depressive symptoms and/or anxiety symptoms to a combinedadministration of a V_(1B) receptor antagonist as described herein and afurther pharmaceutical active compound suitable in the treatment ofdepressive symptoms and/or anxiety symptoms as described herein may alsobe predicted by the methods described herein. Furthermore, the treatmentresponse to any other compound, drug or biomolecule that is capable oftreating depressive symptoms and/or anxiety symptoms in patients whohave an elevated arginine vasopressine (AVP) level and/or elevatedcopeptin level may be also be predicted by methods described herein. Inparticular, the disclosure can be understood to mean that the term“V_(1B) receptor antagonists” can be replaced by any other compound thatinterferes with the V_(1B) receptor mediated pathway and leads to areduction and/or remission of depressive symptoms and/or anxietysymptoms patients with elevated arginine vasopressine (AVP) level and/orelevated copeptin level.

The invention is further described in the following examples which aresolely for the purpose of illustrating specific embodiments of theinvention, and are also not to be construed as limiting the scope of theinvention in any way.

EXAMPLES Example 1

Sample Description

Patients participating in the Munich Antidepressant Response Signature(MARS) project have been included. Selection criteria were:

150 inpatients suffering from unipolar major depression, who weredivided into 75 patients with high vs. low HPA axis dysregulations,each, using matched extremes according to the results of a combineddex/CRH test at the time of admission 123 inpatients with twoconsecutive dex/CRH tests during hospitalisation, the first atadmission, the second on average 60 days thereafter.

Due to partial overlap between patients selected according to the twocriteria, the total number of subjects included in this analysis is 202.Copeptin was measured in the plasma samples of the combined dex/CRH testusing the first specimen, which was obtained under dex suppression, butprior to CRH stimulation.

Associations between Copeptin and Dex/CRH Test Outcome

Patients of the MARS project have been divided into 75 with high and 75with low HPA axis dysregulations according to the results of a firstcombined dex/CRH test, which was conducted on average 6 days afteradmission to the hospital. There was a significant difference betweenboth groups in plasma copeptin levels of the first dex/CRH test (cf.FIG. 1).

This group effect was not found in plasma copeptin levels of the seconddex/CRH test (p=0.595; on average 60 days after admission), althoughthere was still a strong effect on dex/CRH test outcome (e.g., ACTH AUC:p=0.005; cortisol AUC: p<0.001).

Next we tested for associations between plasma copeptin of the first andsecond dex/CRH test and ACTH and cortisol responses to the respectivetest. As can be seen in Table 2, we observe robust positive associationsbetween integrative measures of the ACTH and cortisol response to bothdex/CRH tests (AUC, Max) and copeptin levels. Also the net cortisol, andpartly also the net ACTH responses particularly reflecting CRH effectsshow significant associations with copeptin.

TABLE 2 Associations between ACTH and cortisol responses to the first(on average six days after admission) and the second dex/CRH test (onaverage after 60 days) and respective plasma copeptin levels (N = 194 atthe first dex/CRH test; N = 118 at the second dex/CRH test; resultscorrected for the effects of age and gender). Copeptin @ Copeptin @ 1stDexCRH 2nd DexCRH ACTH Baseline (after dex) Correlation .449 .031p-value .000 .744 ACTH Max (after CRH) Correlation .310 .566 p-value.000 .000 ACTH AUC Correlation .231 .519 p-value .001 .000 ACTH Net AUC(baseline Correlation .000 .574 corr.) p-value .996 .000 CortisolBaseline (after Correlation .053 .209 dex) p-value .462 .025 CortisolMax (after CRH) Correlation .151 .436 p-value .037 .000 Cortisol AUCCorrelation .185 .438 p-value .010 .000 Cortisol Net AUC (baselinCorrelation .233 .451 corr.) p-value .001 .000

Associations between Copeptin and Depression Symptoms

To evaluate the effects of copeptin and HPA axis measures on concurrentdepression symptoms, we evaluated the associations between thesemeasures and the total score on the 21 item Hamilton Depression RatingScale (HAMD) obtained at the test day (or in close proximity to the testday). The results can be found in Table 3.

TABLE 3 Associations between ACTH, cortisol and copeptin responses tothe first (on average six days after admission) and the second dex/CRHtest (on average after 60 days) and depression symptoms evaluated withthe HAMD scale (N = 194 at the first dex/CRH test; N = 118 at the seconddex/CRH test; result corrected for the effects of age and gender). HAMD@ HAMD @ 1st DexCRH 2nd DexCRH ACTH Baseline (after dex) Correlation.169 −.038 p-value .019 .687 ACTH Max (after CRH) Correlation .136 −.104p-value .061 .266 ACTH AUC Correlation .127 −.108 p-value .079 .250 ACTHNet AUC (baseline Correlation .049 −.109 corr.) p-value .504 .244Cortisol Baseline (after Correlation .261 .031 dex) p-value .000 .740Cortisol Max (after CRH) Correlation .162 −.064 p-value .025 .497Cortisol AUC Correlation .197 −.058 p-value .006 .538 Cortisol Net AUC(baselin Correlation .071 −.091 corr.) p-value .327 .329 CopeptinCorrelation −.029 −.121 p-value .687 .197

Associations between Change in Copeptin and Treatment Outcome

In the following analysis we evaluated the change in HPA axis parametersand copeptin between both dex/CRH tests as predictors for depressionoutcome. For this analysis, we included only patients with an HAMD scoreof at least 14 indicating moderate depression severity at the time ofthe first dex/CRH test. Furthermore, only patients with a second dex/CRHtest within the first 8 weeks of hospitalisation were considered(average time of the second dex/CRH test: 31 days after admission).Outcome was evaluated as response after 8 weeks and as remission at theend of hospitalisation. All available data have been included. Theresults are presented in Table 4.

TABLE 4 Associations between change in ACTH, cortisol and copeptinresponses to a second dex/CRH tests after to 8 weeks (on average after31 days) and response after 8 weeks as well as remission at discharge asdepression outcome (N = 209/159 for ACTH and cortisol, N = 52/51 forcopeptin; results corrected for the effects of age and gender). Response@ Remission @ 8 Weeks Discharge ACTH Baseline (after dex) OR 1.05 1.06p-value .112 .161 ACTH Max (after CRH) OR 1.01 1.02 p-value .224 .227ACTH AUC OR 1.01 1.01 p-value .274 .204 ACTH Net AUC (baseline corr.) OR1.01 1.01 p-value .856 .849 Cortisol Baseline (after dex) OR 1.02 1.01p-value .064 .275 Cortisol Max (after CRH) OR 1.01 1.01 p-value .415.045 Cortisol AUC OR 1.01 1.01 p-value .204 .038 Cortisol Net AUC(baseline OR 1.00 1.01 corr.) p-value .788 .075 Copeptin OR 1.00 1.00p-value .965 .975

Summary and Discussion

Dividing depressed inpatients in those with high vs. low HPA axisdysregulations at the time of admission to the hospital resulted in aclear effect on plasma copeptin, which was collected in the first offive blood samples collected during the dex/CRH test. This findingsupports the role of elevated hypothalamic vasopressin levels as a keydriver of HPA axis dysregulations in depression. In line with thisfinding, we observed medium to strong associations between parameters ofthe ACTH and Cortisol response to the dex/CRH test and elevated plasmacopeptin levels.

Example 2

Genetic polymorphisms that influence the extent of the ACTH response inthe combined Dex/CRH test in patients with current moderate to severedepression were identified using genome-wide SNP analysis of epistasiswith genetic variation in the AVPR1B gene, a key player in the pathwaysrelating to the combined Dex/CRH test. These polymorphisms describegenetic variations that in interaction with genetic variation in theAVPR1B gene lead to major depression with CRH hyperdrive. Patientscarrying the alleles/genotypes associated with a larger cortisol or ACTHresponse in the dex/CRH test should therefore profit from V_(1B)antagonist treatment of depression and anxiety.

Patients:

Patients with unipolar or bipolar depression admitted as inpatients tothe Max Planck Institute of Psychiatry (MPI), Munich, Germany, fortreatment of a depressive episode were included in the study. Patientswere diagnosed by psychiatrists according to the Diagnostic andStatistical Manual of Mental Disorders (DSM) IV criteria. Patients withbipolar disorder or depressive disorder due to a general medical orneurological condition were excluded, as were patients with a lifetimediagnosis of drug abuse and depressive symptoms secondary to alcohol orsubstance abuse or dependency. Ethnicity was recorded using aself-report sheet for nationality, first language and ethnicity of thepatient and of all four grandparents.

All patients were Caucasian and part of theMunich-Antidepressant-Response-Signature (MARS) project (Hennings et al.Clinical characteristics and treatment outcome in a representativesample of depressed inpatients—findings from the Munich AntidepressantResponse Signature (MARS) project. J Psychiatr Res. January 2009;43(3):215-229; www.mars-depression.de). They were treated withantidepressant medications according to doctor's choice. Severity ofdepressive symptoms was assessed at admission and at the time of thedex-CRH test by trained raters using the 17-item Hamilton DepressionRating Scale (HAM-D) (Hamilton M. A rating scale for depression. JNeurol Neurosurg Psychiatry. 1960; 23:56-62). 352 patients fulfillingthe criteria for at least a moderate to severe depressive episode(HAM-D>18) at both time points and who had been administered a dex-CRHtest within 10 days of in-patients admission and had genome-wide SNPdata were included in this analysis. The study was approved by theEthics Committee of the Ludwig Maximilians University in Munich,Germany, and written informed consent was obtained from all subjects.

Dex-CRH Test:

The dex-CRH test was administered as described in detail in Heuser etal. Shortly, subjects were pre-treated with 1.5 mg of dexamethasone peros at 11 pm. The following day, at 3 pm, 3.30 pm, 3.45 pm, 4 pm and 4:15pm blood was drawn. An intravenous bolus of 100 ng of human CRH(Ferring, Kiel, Germany) was given at 3.02 pm. Plasma ACTHconcentrations were assessed by an immunometric assay without extraction(Nichols Institute, San Juan Capistrano, Calif.; USA). Theneuroendocrine response to the dex/CRH test was analyzed using the totalarea under the curve (AUC) of the ACTH response.

SNP Genotyping:

After enrollment in the study 40 ml of EDTA blood was drawn from eachpatient. DNA was extracted from fresh blood using the Puregene® wholeblood DNA-extraction kit (Gentra Systems Inc; Minn.).

Genotyping was performed on Illumina Human 610k quad genotyping arrays(Illumina Inc., San Diego, USA) according to the manufacturer's standardprotocols. The average call rate exceeded 99%, with samples below 98%being either retyped or excluded from the study. The reproducibility forsamples genotyped twice was 99.99% or better.

Data Analysis:

To identify genetic predictors for the ACTH response to the dex/CRH testin patients with moderate to severe depression, the full sample of 352patients was used. After natural log transformation of the AUC of theACTH response in the dex-CRH test, an analysis of epistasis (gene bygene interaction with the AVPR1B SNP rs28373064) was used to determineSNPs associated with the quantitative phenotype natural log of the AUCof the ACTH response. This analysis was done genome wide and only SNPswith a P-value of <1*10⁻⁵ were retained for the building of the geneticpredictor. This resulted in a total of 14 SNPs. For the predictionanalysis patients were dichotomized into high vs. low responders byselecting the top and the bottom quartile of the phenotype. This led toa number of 88 patients in each group. For the low responder group thenatural log of the AUC of the ACTH ranged from 5.704 to 6.384, for thehigh responder group the range of the natural log of the AUC of the ACTHranged from 7.399 to 8.980. See the corresponding histogram in FIG. 2for the trait distribution in the two groups.

The 14 SNPs retained were then used predict either ACTH response statussupport vector machine″ approach (implementation DTREG 10.6.21www.dtreg.com). All values were derived from leave-one-outcross-validation.

Results:

The top 14 associations with ACTH response in interaction with AVPR1Bgenetic variation status are given in table 5. The genotypes for the 14SNPs each were then used to predict high vs. low ACTH response statususing interaction with AVPR1B genetic variation applying leave-one-outcross-validation.

TABLE 5 List of 14 SNPs used to predict high vs low ACTH response statusallowing for interaction with genetic variation in the AVPR1B gene.P-value for association with ln AUC ACTH in epistasis with geneticvariation in SNP Chromosome Coordinate_HG18 GeneVariant AVPR1B GeneNamers9880583 chr3 20980315 INTERGENIC 6.31E−005 N/A rs13099050 chr321028194 INTERGENIC 4.50E−005 N/A rs7441352 chr4 55608691 INTERGENIC1.68E−005 N/A rs730258 chr4 68431265 INTRONIC 9.08E−005 TMPRSS11Drs12654236 chr5 169540125 INTERGENIC 9.98E−005 N/A rs17091872 chr819876257 INTERGENIC 9.77E−005 N/A rs12254219 chr10 79113526 INTERGENIC6.05E−005 N/A rs11575663 chr10 115316093 INTRONIC 7.92E−005 HABP2rs7080276 chr10 123112960 INTERGENIC 8.87E−005 N/A rs7416 chr11 104850773PRIME_UTR 5.61E−005 AMPD3 rs12424513 chr12 95088085 INTERGENIC4.20E−005 N/A rs1035050 chr17 44919011 INTERGENIC 9.77E−005 N/Ars9959162 chr18 68100371 INTERGENIC 5.57E−005 N/A rs8088242 chr1868100758 INTERGENIC 6.06E−005 N/A

The results of the prediction are summarized below:

For the prediction of the dichotomized high vs low ACTH response statusin the dex-CRH test the following prediction values in the leave-one-outcross validation were achieved:

ACTH:

-   -   Accuracy=75.00%    -   True positive (TP)=69 (39.2%)    -   True negative (TN)=63 (35.8%)    -   False positive (FP)=25 (14.2%)    -   False negative (FN)=19 (10.8%)    -   Sensitivity=78.41%    -   Specificity=71.59%    -   Geometric mean of sensitivity and specificity=74.92%    -   Positive Predictive Value (PPV)=73.40%    -   Negative Predictive Value (NPV)=76.83%    -   Geometric mean of PPV and NPV=75.10%    -   Precision=73.40%    -   Recall=78.41%    -   F-Measure=0.7582    -   Area under ROC curve (AUC)=0.780475

Summary and Discussion

Using genome-wide SNP association data for the ACTH response in thedex/CRH test, a subset of 14 SNPs was identified that, in conjunctionwith the SNP rs28373064, can be used for an accurate, sensitive andspecific prediction of these phenotypes in patients. Increased ACTHsecretion in this test has been linked to a possible increase in centralCRH/CRHR1 function. It is surprising that genetic polymorphisms, whichact in interaction with genetic variation in the AVPR1B gene, withouttaking into consideration other factors such as endocrine measures, aresuitable predictors of the ACTH response in the dex/CRH test.

These variants may be used to identify patients that may have CRH systemhyperactivity when depressed. Patients with depression or anxietydisorders, classified into the high ACTH response group according to thegenotypes of the presented 14 SNPs and the SNP rs28373064 will be morelikely to respond to V_(1B) antagonist treatment. This allows anenrichment of such patients for V_(1B) antagonist treatment studies whoshould respond to this specific treatment.

1. A method of treating depressive symptoms and/or anxiety symptomscomprising administering an effective amount of a vasopressin receptor1B (V_(1B)) antagonist to a patient having depressive symptoms and/oranxiety symptoms and having an elevated arginine vasopressin (AVP) leveland/or an elevated copeptin level, thereby treating the depressivesymptoms and/or anxiety symptoms in the patient. 2.-3. (canceled)
 4. Themethod of claim 1, wherein the patient has been pre-treated withdexamethasone.
 5. The method of claim 1, wherein the elevated AVP levelis indicated by a copeptin blood concentration of at least 5 pmol/L. 6.(canceled)
 7. The method of claim 1, wherein the elevated AVP level isan AVP concentration of at least 4 pg/ml AVP.
 8. The method of claim 1,wherein the elevated AVP level and/or the elevated copeptin level isdetected by determining the presence or absence of at least onepolymorphic variant in the AVPR1B gene in combination with the presenceor absence of at least one polymorphic variant in the patient's genomeexcluding the AVPR1B gene.
 9. The method of claim 8, wherein thepolymorphic variant in the AVPR1B gene and/or in the patient's genomeexcluding the AVPR1B gene is a single nucleotide polymorphism (SNP). 10.The method of claim 9, wherein the SNP in the AVPR1B gene is SNPrs28373064 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 2, wherein in one or two alleles of thewild-type nucleotide A is replaced by indicator nucleotide G.
 11. Themethod of claim 8, wherein the at least one polymorphic variant in thepatient's genome excluding the AVPR1B gene is selected from the group ofbiomarkers consisting of: SNP rs9880583 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 3, wherein in one or twoalleles the wild-type nucleotide C is replaced by indicator nucleotideG, SNP rs13099050 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 4, wherein in one or two alleles the wild-typenucleotide A is replaced by indicator nucleotide C, SNP rs7441352 whichis represented by a single polymorphic change at position 27 of SEQ IDNO: 5, wherein in one or two alleles the wild-type nucleotide A isreplaced by indicator nucleotide G, SNP rs730258 which is represented bya single polymorphic change at position 27 of SEQ ID NO: 6, wherein inone or two alleles the wild-type nucleotide C is replaced by indicatornucleotide T, SNP rs12654236 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 7, wherein in one or twoalleles the wild-type nucleotide A is replaced by indicator nucleotideG, SNP rs17091872 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 8, wherein in one or two alleles the wild-typenucleotide A is replaced by indicator nucleotide G, SNP rs12254219 whichis represented by a single polymorphic change at position 27 of SEQ IDNO: 9, wherein in one or two alleles the wild-type nucleotide C isreplaced by indicator nucleotide T, SNP rs11575663 which is representedby a single polymorphic change at position 27 of SEQ ID NO: 10, whereinin one or two alleles the wild-type nucleotide A is replaced byindicator nucleotide G, SNP rs7080276 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 11, wherein in one ortwo alleles the wild-type nucleotide A is replaced by indicatornucleotide G, SNP rs7416 which is represented by a single polymorphicchange at position 27 of SEQ ID NO: 12, wherein in one or two allelesthe wild-type nucleotide A is replaced by indicator nucleotide G, SNPrs12424513 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 13, wherein in one or two alleles thewild-type nucleotide C is replaced by indicator nucleotide T, SNPrs1035050 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 14, wherein in one or two alleles thewild-type nucleotide C is replaced by indicator nucleotide T, SNPrs9959162 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 15, wherein in one or two alleles thewild-type nucleotide A is replaced by indicator nucleotide C, and/or SNPrs8088242 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 16, wherein in one or two alleles thewild-type nucleotide A is replaced by indicator nucleotide G.
 12. Themethod of claim 11, wherein the at least one polymorphic variant in thepatient's genome excluding the AVPR1B gene is at least 2 biomarkers ofthe group of biomarkers.
 13. The method of claim 12, wherein the atleast one polymorphic variant in the patient's genome excluding theAVPR1B gene consists of all of the biomarkers of the group ofbiomarkers.
 14. The method of claim 11, wherein the combination of thepresence or absence of SNP rs28373064 with the presence or absence of atleast 1 of the biomarkers of the group of biomarkers is determined. 15.The method of claim 14, wherein the presence of SNP rs28373064 incombination with the presence of SNP rs9880583, SNP rs730258, SNPrs12654236, SNP rs17091872, SNP rs12254219, SNP rs11575663, SNPrs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162 and SNP rs8088242and the absence of SNP rs28373064 in combination with the absence of SNPrs13099050, SNP rs7441352 and SNP rs12424153 is determined.
 16. Themethod of claim 1, wherein the V_(1B) receptor antagonist is selectedfrom the group consisting of SSR149415, Org 52186, ABT-436 and/orABT-558.
 17. The method of claim 1, wherein the V_(1B) receptorantagonist is administered in combination with at least one furtherpharmaceutically active compound suitable for the treatment ofdepressive symptoms and/or anxiety symptoms. 18.-19. (canceled)
 20. Amethod for predicting a treatment response to a V_(1B) receptorantagonist in a patient with depressive symptoms and/or anxiety symptomscomprising the following steps: (i) determining the presence or absenceof at least one polymorphic variant in the AVPR1B gene in a nucleic acidsample of said patient and (ii) determining the presence or absence ofat least one polymorphic variant in the patient's genome excluding theAVPR1B gene in a nucleic acid sample of said patient, wherein thepresence or absence of at least one polymorphic variant in the AVPR1Bgene in combination with the presence or absence of at least onepolymorphic variant in the patient's genome excluding the AVPR1B gene isindicative for the treatment response.
 21. The method of claim 20,wherein the polymorphic variant in the AVPR1B and/or in the patient'sgenome excluding the AVPR1B gene is a single nucleotide polymorphism(SNP).
 22. The method of claim 21, wherein a polymorphic variant in theAVPR1B gene is SNP rs28373064 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 2, wherein in one or twoalleles of the wild-type nucleotide A is replaced by indicatornucleotide G.
 23. The method of claim 20, wherein the at least onepolymorphic variant in the patient's genome excluding the AVPR1B gene isselected from the group of biomarkers consisting of: SNP rs9880583 whichis represented by a single polymorphic change at position 27 of SEQ IDNO: 3, wherein in one or two alleles the wild-type nucleotide C isreplaced by indicator nucleotide G, SNP rs13099050 which is representedby a single polymorphic change at position 27 of SEQ ID NO: 4, whereinin one or two alleles the wild-type nucleotide A is replaced byindicator nucleotide C, SNP rs7441352 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 5, wherein in one or twoalleles the wild-type nucleotide A is replaced by indicator nucleotideG, SNP rs730258 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 6, wherein in one or two alleles the wild-typenucleotide C is replaced by indicator nucleotide T, SNP rs12654236 whichis represented by a single polymorphic change at position 27 of SEQ IDNO: 7, wherein in one or two alleles the wild-type nucleotide A isreplaced by indicator nucleotide G, SNP rs17091872 which is representedby a single polymorphic change at position 27 of SEQ ID NO: 8, whereinin one or two alleles the wild-type nucleotide A is replaced byindicator nucleotide G, SNP rs12254219 which is represented by a singlepolymorphic change at position 27 of SEQ ID NO: 9, wherein in one or twoalleles the wild-type nucleotide C is replaced by indicator nucleotideT, SNP rs11575663 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 10, wherein in one or two alleles thewild-type nucleotide A is replaced by indicator nucleotide G, SNPrs7080276 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 11, wherein in one or two alleles thewild-type nucleotide A is replaced by indicator nucleotide G, SNP rs7416which is represented by a single polymorphic change at position 27 ofSEQ ID NO: 12, wherein in one or two alleles the wild-type nucleotide Ais replaced by indicator nucleotide G, SNP rs12424513 which isrepresented by a single polymorphic change at position 27 of SEQ ID NO:13, wherein in one or two alleles the wild-type nucleotide C is replacedby indicator nucleotide T, SNP rs1035050 which is represented by asingle polymorphic change at position 27 of SEQ ID NO: 14, wherein inone or two alleles the wild-type nucleotide C is replaced by indicatornucleotide T, SNP rs9959162 which is represented by a single polymorphicchange at position 27 of SEQ ID NO: 15, wherein in one or two allelesthe wild-type nucleotide A is replaced by indicator nucleotide C, and/orSNP rs8088242 which is represented by a single polymorphic change atposition 27 of SEQ ID NO: 16, wherein in one or two alleles thewild-type nucleotide A is replaced by indicator nucleotide G.
 24. Themethod of claim 23, wherein the at least one polymorphic variant in thepatient's genome excluding the AVPR1B gene is at least 2 biomarkers ofthe group of biomarkers.
 25. The method of claim 24, wherein the atleast one polymorphic variant in the patient's genome excluding theAVPR1B gene consists of all of the biomarkers of the group ofbiomarkers.
 26. The method of claim 23, wherein the combination of thepresence or absence of SNP rs28373064 with the presence or absence of atleast 1 biomarker of the group of biomarkers is determined.
 27. Themethod of claim 26, wherein the presence of SNP rs28373064 incombination with the presence of SNP rs9880583, SNP rs730258, SNPrs12654236, SNP rs17091872, SNP rs12254219, SNP rs11575663, SNPrs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162 and SNP rs8088242and the absence of SNP rs28373064 in combination with the absence of SNPrs13099050, SNP rs7441352 and SNP rs12424153 is determined.
 28. A methodfor predicting a treatment response to a V_(1B) receptor antagonist in apatient with depressive symptoms and/or anxiety symptoms, wherein thecopeptin concentration in a blood sample of said patient is determinedand/or the AVP concentration in a sample of cerebrospinal fluid of saidpatient is determined and wherein an elevated copeptin and/or anelevated AVP concentration is indicative for a patient responding to atreatment with a V_(1B) receptor antagonist.
 29. The method of claim 28,further comprising a step of pre-treating the patient with dexamethasoneand subsequently determining the copeptin concentration in the bloodsample and/or the AVP concentration in the sample of cerebrospinalfluid.
 30. The method of claim 29, further comprising subjecting thepatient to at least one combined dexamethasone/corticotropin test(dex/CRH test).
 31. The method of claim 28, wherein the elevatedcopeptin concentration indicative for a patient responding to atreatment with a vasopressin receptor antagonist is at least 5 pmol/L.32. The method of claim 28, wherein the elevated AVP concentrationindicative for a patient responding to a treatment with a V_(1B)receptor antagonist is at least 4 pg/ml AVP.